Chiral n-heterocyclic phosphorodiamidic acids (NHPAS) and derivatives as novel bronsted acid catalysts

ABSTRACT

Provided herein are diaryl and arylalkyl phosphonates, useful as intermediates in, for example, the synthesis of leukocyte elastase inhibitors, potassium channel modulators, chemiluminescence materials, and flame retardants, and methods for making same. Also provided are N-heterocyclic phosphorodiamidic acids (NHPAs) useful in reactions such as, for example, in the preparation of diaryl and arylalkyl phosphonates. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under 35 U.S.C. § 371 ofInternational Application No. PCT/US2018/037868, filed on Jun. 15, 2018,which claims the benefit of U.S. Provisional Application No. 62/521,086,filed on Jun. 16, 2017, U.S. Provisional Application No. 62/566,834,filed on Oct. 2, 2017, and U.S. Provisional Application No. 62/568,645,filed on Oct. 5, 2017, the contents of which are incorporated herein byreference in their entireties.

BACKGROUND

The activation of a small molecule by a chiral organocatalyst has beenrealized as one of the most powerful tools for asymmetric synthesis(Taylor and Jacobsen (2006) Angew. Chem., Int. Ed. 45: 1520-1543; Yu andWang (2008) Chem.-Asian J. 3: 516-532; Doyle and Jacobsen (2007) Chem.Rev. 107: 5713-5743; Parmar et al. (2014) Chem. Rev. 114: 9047-9153).Accordingly, a large number of organic chiral catalysts have beendeveloped and successfully applied in the stereoselective transformationof small organic molecules (Bernardi et al. (2012) Org. Biomol. Chem.10: 2911-2922). Among them, Brønsted acids such as BINOL-derived (Parmaret al. (2014) Chem. Rev. 114: 9047-9153; Shibasaki and Matsunaga (2006)Chem. Soc. Rev. 35: 269-279; Chen et al. (2003) Chem. Rev. 103:3155-3212) and SPINOL-derived (Xie and Zhou (2008) Acc. Chem. Res. 41:581-593; Zhu and Zhou (2012) Acc. Chem. Res. 45: 1365-1377) phosphoricacids have demonstrated efficiency and versatility in many synthetictransformations. However, the synthesis of those phosphoric acidderivatives requires a multitude of steps with low overall yields.Consequently, the development phosphoric acid catalysts that are highlyreactive and accessible via a concise synthesis is highly desirable.These needs and others are met by the present invention.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates toN-heterocyclic phosphorodiamidic acids and methods of using thesecomplexes for the generation of, for example, ortho-quinone methides,which are versatile building blocks of pharmaceuticals and otherbiologically significant small molecules.

Disclosed are compounds having a structure represented by a formulaselected from:

wherein each occurrence of

is a single covalent bond; wherein each of R^(1a), R^(1b), R^(1a′), andR^(1b′), when present, is independently selected from hydrogen, C1-C4alkyl, and Ar¹; wherein each occurrence of Ar¹, when present, isindependently selected from C6-C14 aryl and 4-10 membered heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; orwherein each of R^(1a) and R^(1b) are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a 5- to6-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; or wherein each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- to 6-membered cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R², R³,R^(2′), and R^(3′), when present, are independently selected from—Si(R^(20a))(R^(20b))R^(20c), Ar², and —C(R^(21a))(R^(21b))Ar²; whereineach occurrence of R^(20a), R^(20b), and R^(20c), when present, isindependently selected from C1-C4 alkyl and phenyl; wherein eachoccurrence of R^(21a) and R^(21b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar²,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl; or wherein each occurrence of

is a double covalent bond; wherein each of R^(1a) and R² are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³; whereineach occurrence of R^(22a) and R^(22b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar³,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³; wherein each of R^(1b) and R³ are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴; whereineach occurrence of R^(23a) and R^(23b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein occurrence of Ar⁴, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; and wherein each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴; wherein R⁴, when present, is selected from —OHand —NHR²⁴; wherein R²⁴, when present, is an amine protecting group,provided that when the compound has a structure represented by aformula:

wherein each of R^(1a) and R^(1b) are hydrogen and R² and R³ are Ar²,then each occurrence of Ar² is substituted with 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or wherein each of R^(1a) and R^(1b) arehydrogen, R² and R³ are independently —C(R^(21a))(R^(21b))Ar², and Ar²is unsubstituted C10 aryl, then each occurrence of R^(21a) is nothydrogen, or wherein each of R^(1a) and R^(1b) are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 6-membered cycloalkyl, R² and R³ are independently—C(R^(21a))(R^(21b))Ar², and Ar² is unsubstituted C10 aryl, then eachoccurrence of R^(21a) is not hydrogen, or a salt thereof.

Also disclosed are compounds selected from:

or a salt thereof.

Also disclosed are compounds selected from:

or a salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein n is selected from 0 and 1; wherein each of R^(101a) andR^(101b) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that at least oneof R^(101a) and R^(101b) is —OH, —SH, or C1-C4 alkylamino; wherein eachof R^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R¹⁰³ is selected from C4-C8 alkyl and Ar¹⁰¹,provided that when R¹⁰³ is C4-C8 alkyl, then either: (a) at least one ofR^(101a) and R^(101b) is —SH or C1-C4 alkylamino, or (b) then R^(101b)is —OH; wherein Ar¹⁰¹, when present, is selected from C6-C10 aryl andC5-C6 heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl; wherein R¹⁰⁴ is selected from C1-C4 alkoxy andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; andwherein R¹⁰⁵ is C1-C4 alkyl, provided that when n is 0, R^(101a) is —OH,R¹⁰³ is C6 aryl, R¹⁰⁴ is ethoxy, and R¹⁰⁵ is ethyl, then either: (c) atleast two of R^(101b), R^(102a), R^(102b), and R^(102c) are nothydrogen, (d) R¹⁰³ is substituted with 2 or 3 groups, or (e) at leastone of R^(101b), R^(201a), R^(102b), and R^(102c) is not hydrogen andR¹⁰³ is substituted with 1, 2, or 3 groups; and provided that when n is0, R^(101b) is —OH, and R¹⁰³ is C6 aryl or C6 heteroaryl, then either:(f) each of R^(102a) and R^(102b) is hydrogen; or (g) one of R^(102a)and R^(102b) is hydrogen and R¹⁰⁴ is not the same as —OR⁵, or apharmaceutically acceptable salt thereof.

Also disclosed are compounds selected from:

or a pharmaceutically acceptable salt thereof.

Also disclosed are methods of making a disclosed compound.

Also disclosed are methods of using a disclosed compound.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows a representative schematic of a diastereoselectivephospha-Michael addition reaction of dialkyl phenylphosphites to o-QMs.

FIG. 2A shows a representative schematic illustrating the purificationof diastereomers by flash column chromatography. FIG. 2B shows arepresentative Newman projection of a phosphonium intermediate and theproposed diastereoselectivity.

FIG. 3A and FIG. 3B show representative data from an in situ ¹H NMRstudy of a crude reaction mixture. Specifically, FIG. 3A shows an ¹H NMRspectrum of the reaction mixture of the scheme as shown in the sectionentitled “In Situ NMR Study.” FIG. 3B shows an ¹H NMR spectrum of thereaction mixture of the scheme as shown in the section entitled “In SituNMR Study” with the addition of iPrOH.

FIG. 4A and FIG. 4B show representative data from an in situ ¹³C NMRstudy of a crude reaction mixture. Specifically, FIG. 4A shows an ¹³CNMR spectrum of the reaction mixture of the scheme as shown in thesection entitled “In Situ NMR Study.” FIG. 4B shows an ¹³C NMR spectrumof the reaction mixture of the scheme as shown in the section entitled“In Situ NMR Study” with the addition of iPrOH.

FIG. 5 shows representative data illustrating the scope of thephospha-Michael reaction as disclosed herein.

FIG. 6 shows a representative proposed mechanism of the phospha-Michaelreaction as disclosed herein.

FIG. 7 shows a representative schematic illustrating the syntheticutility of diaryl phosphonate adducts.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate aspects, can also beprovided in combination in a single aspect. Conversely, various featuresof the disclosure which are, for brevity, described in the context of asingle aspect, can also be provided separately or in any suitablesubcombination.

For the terms “for example” and “such as,” and grammatical equivalencesthereof, the phrase “and without limitation” is understood to followunless explicitly stated otherwise.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

All compounds, and salts thereof (e.g., pharmaceutically acceptablesalts), can be found together with other substances such as water andsolvents (e.g., hydrates and solvates).

Compounds provided herein also can include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers that are isomeric protonation stateshaving the same empirical formula and total charge. Example prototropictautomers include ketone-enol pairs, amide-imidic acid pairs,lactam-lactim pairs, enamine-imine pairs, and annular forms where aproton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds provided herein can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include hydrogen, tritium, anddeuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Also provided herein are pharmaceutically acceptable salts of thecompounds described herein. As used herein, the term “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the compounds provided herein include theconventional non-toxic salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. The pharmaceuticallyacceptable salts of the compounds provided herein can be synthesizedfrom the parent compound that contains a basic or acidic moiety byconventional chemical methods. Generally, such salts can be prepared byreacting the free acid or base forms of these compounds with astoichiometric amount of the appropriate base or acid in water or in anorganic solvent, or in a mixture of the two. In various aspects, anon-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol,ethanol, iso-propanol, or butanol) or acetonitrile (ACN) can be used.Lists of suitable salts are found in Remington's PharmaceuticalSciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418and Journal of Pharmaceutical Science, 66, 2 (1977). Conventionalmethods for preparing salt forms are described, for example, in Handbookof Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH,2002.

In various aspects, the compounds provided herein, or salts thereof, aresubstantially isolated. By “substantially isolated” is meant that thecompound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

As used herein, chemical structures that contain one or morestereocenters depicted with dashed and bold bonds (i.e.,

) are meant to indicate absolute stereochemistry of the stereocenter(s)present in the chemical structure. As used herein, bonds symbolized by asimple line do not indicate a stereo-preference. Unless otherwiseindicated to the contrary, chemical structures, which include one ormore stereocenters, illustrated herein without indicating absolute orrelative stereochemistry encompass all possible stereoisomeric forms ofthe compound (e.g., diastereomers and enantiomers) and mixtures thereof.Structures with a single bold or dashed line, and at least oneadditional simple line, encompass a single enantiomeric series of allpossible diastereomers.

Resolution of racemic mixtures of compounds can be carried out usingappropriate methods. An exemplary method includes fractionalrecrystallization using a chiral resolving acid that is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, orthe various optically active camphorsulfonic acids such ascamphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofmethylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent compositions canbe determined by one skilled in the art.

The expressions “ambient temperature” and “room temperature” as usedherein are understood in the art and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, for example, a temperature fromabout 20° C. to about 30° C.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range thatincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl,” employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In various aspects, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In various aspects,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In various aspects, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylene,” employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl,butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl, and the like. In various aspects, the alkylenemoiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbonatoms.

As used herein, the term “C_(n-m) alkoxy,” employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),tert-butoxy, and the like. In various aspects, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In various aspects, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In various aspects, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino,” employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In various aspects, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylthio” refers to a group offormula —S-alkyl, wherein the alkyl group has n to m carbon atoms. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)— alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In various aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl,” employed alone or in combinationwith other terms, refers to a —C(═O)— group, which may also be writtenas C(O).

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “C₁₋₃ alkoxy-C₁₋₃ alkyl” refers to a group offormula —(C₁₋₃ alkylene)-O(C₁₋₃ alkyl).

As used herein, the term “carboxy” refers to a group of formula —C(O)OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In various aspects, each alkyl groupindependently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In various aspects, each alkyl groupindependently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In various aspects,the halo group is F or Cl.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In various aspects, the haloalkoxy group is fluorinated only. Invarious aspects, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) haloalkyl,” employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In various aspects, the haloalkylgroup is fluorinated only. In various aspects, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “amine base” refers to a mono-substituted aminegroup (i.e., primary amine base), di-substituted amine group (i.e.,secondary amine base), or a tri-substituted amine group (i.e., tertiaryamine base). Example mono-substituted amine bases include methyl amine,ethyl amine, propyl amine, butyl amine, and the like. Exampledi-substituted amine bases include dimethylamine, diethylamine,dipropylamine, dibutylamine, pyrrolidine, piperidine, azepane,morpholine, and the like. In various aspects, the tertiary amine has theformula N(R′)₃, wherein each R′ is independently C₁₋₆ alkyl, 3-10 membercycloalkyl, 4-10 membered heterocycloalkyl, 1-10 membered heteroaryl,and 5-10 membered aryl, wherein the 3-10 member cycloalkyl, 4-10membered heterocycloalkyl, 1-10 membered heteroaryl, and 5-10 memberedaryl are optionally substituted by 1, 2, 3, 4, 5, or 6 C₁₋₆ alkylgroups. Example tertiary amine bases include trimethylamine,triethylamine, tripropylamine, triisopropylamine, tributylamine,tri-tert-butylamine, N,N-dimethylethanamine,N-ethyl-N-methylpropan-2-amine, N-ethyl-N-isopropylpropan-2-amine,morpholine, N-methylmorpholine, and the like. In various aspects, theterm “tertiary amine base” refers to a group of formula N(R)₃, whereineach R is independently a linear or branched C₁₋₆ alkyl group.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10ring-forming carbons (C₃₋₁₀). Ring-forming carbon atoms of a cycloalkylgroup can be optionally substituted by oxo or sulfido (e.g., C(O) orC(S)). Cycloalkyl groups also include cycloalkylidenes. Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbomyl, norpinyl, norcarnyl, and the like. Invarious aspects, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl, or adamantyl. In various aspects, thecycloalkyl has 6-10 ring-forming carbon atoms. In various aspects,cycloalkyl is cyclohexyl or adamantyl. Also included in the definitionof cycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of cyclopentane, cyclohexane, andthe like. A cycloalkyl group containing a fused aromatic ring can beattached through any ring-forming atom including a ring-forming atom ofthe fused aromatic ring.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkylgroups can also include spirocycles. Example heterocycloalkyl groupsinclude pyrrolidin-2-one, 1,3-isoxazolidin-2-one, pyranyl,tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, andthe like. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido(e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group canbe attached through a ring-forming carbon atom or a ring-formingheteroatom. In various aspects, the heterocycloalkyl group contains 0 to3 double bonds. In various aspects, the heterocycloalkyl group contains0 to 2 double bonds. Also included in the definition of heterocycloalkylare moieties that have one or more aromatic rings fused (i.e., having abond in common with) to the cycloalkyl ring, for example, benzo orthienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. In various aspects, the heterocycloalkyl has 4-10, 4-7 or4-6 ring atoms with 1 or 2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur and having one or more oxidized ringmembers.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In various aspects, arylgroups have from 6 to about 20 carbon atoms, from 6 to about 15 carbonatoms, or from 6 to about 10 carbon atoms. In various aspects, the arylgroup is a substituted or unsubstituted phenyl.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In various aspects, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In various aspects, any ring-forming Nin a heteroaryl moiety can be an N-oxide. In various aspects, theheteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In variousaspects, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ringmembers independently selected from nitrogen, sulfur and oxygen. Invarious aspects, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

At certain places, the definitions or aspects refer to specific rings(e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

As used herein, the term “electron withdrawing group” (EWG), employedalone or in combination with other terms, refers to an atom or group ofatoms substituted onto a 7-system (e.g., substituted onto an aryl orheteroaryl ring) that draws electron density away from the 7-systemthrough induction (e.g., withdrawing electron density about a σ-bond) orresonance (e.g., withdrawing electron density about a π-bond orπ-system). Example electron withdrawing groups include, but are notlimited to, halo groups (e.g., fluoro, chloro, bromo, iodo), nitriles(e.g., —CN), carbonyl groups (e.g., aldehydes, ketones, carboxylicacids, acid chlorides, esters, and the like), nitro groups (e.g., —NO₂),haloalkyl groups (e.g., —CH₂F, —CHF₂, —CF₃, and the like), alkenylgroups (e.g., vinyl), alkynyl groups (e.g., ethynyl), sulfonyl groups(e.g., S(O)R, S(O)₂R), sulfonate groups (e.g., —SO₃H), and sulfonamidegroups (e.g., S(O)N(R)₂, S(O)₂N(R)₂). In various aspects, the electronwithdrawing group is selected from the group consisting of halo, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₃ haloalkyl, CN, NO₂, C(═O)OR^(a1)C(═O)R^(b1),C(═O)NR^(c1)R^(d1), C(═O)SR^(e1), —NR^(c1)S(O)R^(e1),—NR^(c1)S(O)₂R^(e1), S(═O)R^(e1), S(═O)₂R^(e1), S(═O)NR^(c1)R^(d1),S(═O)₂NR^(c1)R^(d1), and P(O)(OR^(a1))₂. In various aspects, theelectron withdrawing group is selected from the group consisting ofC(═O)OR^(a1), C(═O)R^(b1), C(═O)NR^(c1)R^(d1), C(═O)SR^(e1),S(═O)R^(e1), S(═O)₂R^(e1), S(═O)NR^(c1)R^(d1), and S(═O)₂NR^(c1)R^(d1).In various aspects, the electron withdrawing group is C(═O)OR^(a1). Invarious aspects, the electron withdrawing group is C(═O)OR^(a1), whereinR^(a1) is C₁₋₆ alkyl or (C₆₋₁₀ aryl)-C₁₋₃ alkylene. In various aspects,the electron withdrawing group is an ester.

Preparation of the compounds described herein can involve a reaction inthe presence of an acid or a base. Example acids can be inorganic ororganic acids and include, but are not limited to, strong and weakacids. Example acids include, but are not limited to, hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonicacid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid,trifluoroacetic acid, and nitric acid. Example weak acids include, butare not limited to, acetic acid, propionic acid, butanoic acid, benzoicacid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid,octanoic acid, nonanoic acid, and decanoic acid. Example bases include,without limitation, lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate,sodium bicarbonate, and amine bases. Example strong bases include, butare not limited to, hydroxide, alkoxides, metal amides, metal hydrides,metal dialkylamides and arylamines, wherein; alkoxides include lithium,sodium and potassium salts of methyl, ethyl and t-butyl oxides; metalamides include sodium amide, potassium amide and lithium amide; metalhydrides include sodium hydride, potassium hydride and lithium hydride;and metal dialkylamides include lithium, sodium, and potassium salts ofmethyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, trimethylsilyland cyclohexyl substituted amides (e.g., lithiumN-isopropylcyclohexylamide).

The following abbreviations may be used herein: AcOH (acetic acid); aq.(aqueous); atm. (atmosphere(s)); Br₂ (bromine); Bn (benzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DCM(dichloromethane); DMF (N,N-dimethylformamide); Et (ethyl); Et₂O(diethyl ether); EtOAc (ethyl acetate); EtOH (ethanol); EWG (electronwithdrawing group); g (gram(s)); h (hour(s)); H₂ (hydrogen gas); HCl(hydrochloric acid/hydrogen chloride); HPLC (high performance liquidchromatography); H₂SO₄ (sulfuric acid); Hz (hertz); I₂ (iodine); IPA(isopropyl alcohol); J (coupling constant); KOH (potassium hydroxide);K₃PO₄ (potassium phosphate); LCMS (liquid chromatography-massspectrometry); LiICA (lithium N-isopropylcyclohexylamide); m(multiplet); M (molar); MS (Mass spectrometry); Me (methyl); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); N (normal); NaBH₃CN (sodiumcyanoborohydride); NHP (N-heterocyclic phosphine); NHP—Cl(N-heterocyclic phosphine chloride); Na₂CO₃ (sodium carbonate); NaHCO₃(sodium bicarbonate); NaOH (sodium hydroxide); Na₂SO₄ (sodium sulfate);nM (nanomolar); NMR (nuclear magnetic resonance spectroscopy); PCl₃(trichlorophosphine); PMP (4-methoxyphenyl); RP-HPLC (reverse phase highperformance liquid chromatography); t (triplet or tertiary); t-Bu(tert-butyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF(tetrahydrofuran); TLC (thin layer chromatography); μg (microgram(s));μL (microliter(s)); μM (micromolar); wt % (weight percent).

B. N-Heterocyclic Phosphorodiamidic Acid Reagents

In one aspect, the invention relates to compounds useful as Brønstedacid catalysts. More specifically, the disclosed N-heterocyclicphosphorodiamidic acids (NHPAs) are useful in, for example, promotingphospha-Michael addition reaction of trialkylphosphites to in situgenerated ortho-quinone methides (o-QMs) for the construction of diarylphosphonates. As provided herein, one application of NHPAs in organicsynthesis is in the formation of diaryl and arylalkyl phosphonates.Diaryl and arylalkyl phosphonates have demonstrated a broad spectrum ofbiological activities including, but not limited to, as human prostaticacid phosphatase inhibitors, leukocyte elastase inhibitors, and calciumantagonists. Additionally, diaryl and arylalkyl phosphonates are usefulin, for example, the preparation of chemiluminescence materials andflame retardants.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula selected from:

wherein each occurrence of

is a single covalent bond; wherein each of R^(1a), R^(1b), R^(1a′), andR^(1b′), when present, is independently selected from hydrogen, C1-C4alkyl, and Ar¹; wherein each occurrence of Ar¹, when present, isindependently selected from C6-C14 aryl and 4-10 membered heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; orwherein each of R^(1a) and R^(1b) are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a 5- to6-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; or wherein each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- to 6-membered cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R², R³,R^(2′), and R^(3′), when present, are independently selected from—Si(R^(20a))(R^(20b))R^(20c), Ar², and —C(R^(21a))(R^(21b))Ar²; whereineach occurrence of R^(20a), R^(20b), and R^(20c), when present, isindependently selected from C1-C4 alkyl and phenyl; wherein eachoccurrence of R^(21a) and R^(21b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar²,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl; or wherein each occurrence of

is a double covalent bond; wherein each of R^(1a) and R² are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³; whereineach occurrence of R^(22a) and R^(22b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar³,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³; wherein each of R^(1b) and R³ are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴; whereineach occurrence of R^(23a) and R^(23b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein occurrence of Ar⁴, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; and wherein each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴; wherein R⁴, when present, is selected from —OHand —NHR²⁴; wherein R²⁴, when present, is an amine protecting group,provided that when the compound has a structure represented by aformula:

wherein each of R^(1a) and R^(1b) are hydrogen and R² and R³ are Ar²,then each occurrence of Ar² is substituted with 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or wherein each of R^(1a) and R^(1b) arehydrogen, R² and R³ are independently —C(R^(21a))(R^(21b))Ar² and Ar² isunsubstituted C10 aryl, then each occurrence of R^(21a) is not hydrogen,or wherein each of R^(1a) and R^(1b) are optionally covalently bondedtogether and, together with the intermediate atoms, comprise anunsubstituted 6-membered cycloalkyl, R² and R³ are independently—C(R^(21a))(R^(21b))Ar², and Ar² is unsubstituted C10 aryl, then eachoccurrence of R^(21a) is not hydrogen, or a salt thereof.

Also disclosed are compounds selected from:

or a salt thereof.

Also disclosed are compounds selected from:

or a salt thereof.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula:

wherein R³¹ is selected from C1-C4 alkyl, Ar³, and—C(R^(22a))(R^(22b))Ar³; and wherein R³² is selected from C1-C4 alkyl,Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound has a structure represented by aformula selected from:

wherein each of R³¹ and R^(31′), when present, is independently selectedfrom C1-C4 alkyl, Ar³, and —C(R^(22a))(R^(22b))Ar³; and wherein each ofR³² and R^(32′), when present, is independently selected from C1-C4alkyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound has a structure represented by aformula selected from:

wherein each occurrence of R², R^(2′), R³, and R^(3′) is simultaneouslya structure selected from:

In a further aspect, the compound has a structure represented by aformula:

wherein each occurrence of R³³, R^(33′), R³⁴, and R^(34′) issimultaneously a structure selected from:

In a further aspect, the compound has a structure represented by aformula:

wherein each occurrence of R³¹, R^(31′), R³², and R^(32′) issimultaneously selected from methyl, isopropyl, t-butyl, phenyl, andbenzyl.

In a further aspect,

is a single covalent bond. In a still further aspect,

is a double covalent bond.

a. R^(1A), R^(1B), R^(1A′), and R^(1B′) Groups

In one aspect, each of R^(1a), R^(1b), R^(1a′), and R^(1b′), whenpresent, is independently selected from hydrogen, C1-C4 alkyl, and Ar¹.In a further aspect, each of R^(1a), R^(1b), R^(1a′), and R^(1b′), whenpresent, is hydrogen.

In one aspect, each of R^(1a) and R^(1b) are optionally covalentlybonded together and, together with the intermediate atoms, comprise a 5-to 6-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- to 6-membered cycloalkyl substitutedwith 0, 1, or 2 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each of R^(1a) and R^(1b) are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- to 6-memberedcycloalkyl substituted with 0 or 1 group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each of R^(1a) and R^(1b) are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- to 6-memberedcycloalkyl monosubstituted with a group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each of R^(1a) and R^(1b) are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted 5- to6-membered cycloalkyl.

In one aspect, each of R^(1a′) and R^(1b′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- to 6-membered cycloalkyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a further aspect, each of R^(1a′) andR^(1b′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- to 6-memberedcycloalkyl substituted with 0, 1, or 2 groups independently selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In astill further aspect, each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- to 6-membered cycloalkyl substitutedwith 0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each of R^(1a′)and R^(1b′), when present, are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5- to 6-memberedcycloalkyl monosubstituted with a group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each of R^(1a′) and R^(1b′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5- to 6-membered cycloalkyl.

In one aspect, each of R^(1a) and R² are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a 5- or6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a further aspect,each of R^(1a) and R² are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl substituted with 0 or 1 groups independently selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a) and R²are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In aneven further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5- or 6-membered heterocycloalkyl.

In one aspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In afurther aspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0 or 1 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted 5- or6-membered heterocycloalkyl.

In one aspect, each of R^(1b) and R³ are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a 5- or6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a further aspect,each of R^(1b) and R³ are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b) and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5- or 6-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b) and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In aneven further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5- or 6-membered heterocycloalkyl.

In one aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In afurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet afurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl monosubstituted with agroup selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an even furtheraspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise an unsubstituted 5- or 6-membered heterocycloalkyl.

In a further aspect, each of R^(1a) and R^(1b) is independently selectedfrom hydrogen, C1-C4 alkyl, and Ar¹. In a still further aspect, each ofR^(1a) and R^(1b) is independently selected from hydrogen, methyl,ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, andAr. In yet a further aspect, each of R^(1a) and R^(1b) is independentlyselected from hydrogen, methyl, ethyl, isopropyl, n-propyl, and Ar¹. Inan even further aspect, each of R^(1a) and R^(1b) is independentlyselected from hydrogen, methyl, ethyl, and Ar¹. In a still furtheraspect, each of R^(1a) and R^(1b) is independently selected fromhydrogen, methyl, isopropyl, n-propyl, and Ar¹.

In a further aspect, each of R^(1a) and R^(1b) is independently selectedfrom hydrogen and Ar¹.

In a further aspect, each of R^(1a) and R^(1b) are the same. In a stillfurther aspect, each of R^(1a) and R^(1b) is Ar¹. In yet a furtheraspect, each of R^(1a) and R^(1b) is phenyl. In an even further aspect,each of R^(1a) and R^(1b) is unsubstituted phenyl. In yet a furtheraspect, each of R^(1a) and R^(1b) is hydrogen. In a still furtheraspect, each of R^(1a) and R^(1b) are different.

In a further aspect, each of R^(1a′) and R^(1b′), when present, isindependently selected from hydrogen, C1-C4 alkyl, and Ar¹. In a stillfurther aspect, each of R^(1a′) and R^(1b′), when present, isindependently selected from hydrogen, methyl, ethyl, isopropyl,n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, and Ar¹. In yet afurther aspect, each of R^(1a) and R^(1b), when present, isindependently selected from hydrogen, methyl, ethyl, isopropyl,n-propyl, and Ar¹. In an even further aspect, each of R^(1a′) andR^(1b′), when present, is independently selected from hydrogen, methyl,ethyl, and Ar¹. In a still further aspect, each of R^(1a′) and R^(1b′),when present, is independently selected from hydrogen, methyl,isopropyl, n-propyl, and Ar¹.

In a further aspect, each of R^(1a′) and R^(1b′), when present, isindependently selected from hydrogen and Ar¹.

In a further aspect, each of R^(1a′) and R^(1b′), when present, are thesame. In a still further aspect, each of R^(1a′) and R^(1b), whenpresent, is Ar¹. In yet a further aspect, each of R^(1a) and R^(1b′),when present, is phenyl. In an even further aspect, each of R^(1a′) andR^(1b′), when present, is unsubstituted phenyl. In yet a further aspect,each of R^(1a′) and R^(1b′), when present, is hydrogen. In an evenfurther aspect, each of R^(1a′) and R^(1b′), when present, aredifferent.

In a further aspect, each of R^(1a) and R^(1b) are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered cycloalkyl substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each of R^(1a) andR^(1b) are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered cycloalkyl substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered cycloalkyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise an unsubstituted 5-membered cycloalkyl.

In a further aspect, each of R^(1a) and R^(1b) are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered cycloalkyl substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each of R^(1a) andR^(1b) are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered cycloalkyl substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered cycloalkyl monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each of R^(1a) and R^(1b) areoptionally covalently bonded together and, together with theintermediate atoms, comprise an unsubstituted 6-membered cycloalkyl.

In a further aspect, each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered cycloalkyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each ofR^(1a′) and R^(1b′), when present, are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a5-membered cycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each of R^(1a′) and R^(1b′), whenpresent, are optionally covalently bonded together and, together withthe intermediate atoms, comprise a 5-membered cycloalkyl substitutedwith 0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, each of R^(1a′)and R^(1b′), when present, are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5-memberedcycloalkyl monosubstituted with a group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each of R^(1a′) and R^(1b′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5-membered cycloalkyl.

In a further aspect, each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered cycloalkyl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, each ofR^(1a′) and R^(1b′), when present, are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a6-membered cycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each of R^(1a) and R^(1b), whenpresent, are optionally covalently bonded together and, together withthe intermediate atoms, comprise a 6-membered cycloalkyl substitutedwith 0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, each of R^(1a′)and R^(1b), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-membered cycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each of R^(1a′)and R^(1b′), when present, are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an unsubstituted6-membered cycloalkyl.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet a further aspect,each of R^(1a) and R² are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5-membered heterocycloalkyl.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a) and R²are optionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In an even furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted oxazolidinyl.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet a further aspect,each of R^(1a) and R² are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 6-membered heterocycloalkyl.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 1 group selected from C1-C4alkyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still further aspect, eachof R^(1a) and R² are optionally covalently bonded together and, togetherwith the intermediate atoms, comprise a 5-membered heterocycloalkylsubstituted with 1 group selected from methyl, ethyl, isopropyl,n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a) and R²are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, isopropyl, n-propyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 1 group selected from C1-C4 alkyl, Ar³,and —C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a)and R² are optionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 1 groupselected from methyl, ethyl, isopropyl, n-propyl, isobutyl, n-butyl,sec-butyl, t-butyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet furtheraspect, each of R^(1a) and R² are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, isopropyl,n-propyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In an even further aspect,each of R^(1a) and R² are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 1 groupselected from methyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1a) and R² are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 1 group selected from C1-C4alkyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still further aspect, eachof R^(1a) and R² are optionally covalently bonded together and, togetherwith the intermediate atoms, comprise a 6-membered heterocycloalkylsubstituted with 1 group selected from methyl, ethyl, isopropyl,n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a) and R²are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, isopropyl, n-propyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a) andR² are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet a further aspect,each of R^(1a′) and R^(2′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R²²)Ar³. In an even further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted5-membered heterocycloalkyl.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet afurther aspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise an oxazolidinyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an unsubstituted oxazolidinyl.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³. In yet a further aspect,each of R^(1a′) and R^(2′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted6-membered heterocycloalkyl.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from C1-C4 alkyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,isopropyl, n-propyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In an evenfurther aspect, each of R^(1a) and R², when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, ethyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 1 groupselected from C1-C4 alkyl, Ar³, and —C(R^(22a))(R²)Ar³. In a stillfurther aspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise an oxazolidinyl substituted with 1 group selected from methyl,ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, Ar³,and —C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a′)and R^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, isopropyl,n-propyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In an even further aspect,each of R^(1a′) and R^(2′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 1 group selected from methyl, ethyl, Ar³,and —C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′)and R^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, Ar³, and—C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from C1-C4 alkyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl, t-butyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R^(1a′) andR^(2′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,isopropyl, n-propyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In an evenfurther aspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 6-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, ethyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In a still furtheraspect, each of R^(1a′) and R^(2′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 6-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b) and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect,each of R^(1b) and R³ are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of R^(1b) andR³ are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 5-membered heterocycloalkyl.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b) and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b) and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an even furtheraspect, each of Rib and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted oxazolidinyl.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b) and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect,each of R^(1b) and R³ are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of R^(1b) andR³ are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 6-membered heterocycloalkyl.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 1 group selected from C1-C4alkyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, eachof R^(1b) and R³ are optionally covalently bonded together and, togetherwith the intermediate atoms, comprise a 5-membered heterocycloalkylsubstituted with 1 group selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b) and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, n-propyl, isopropyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of Rib and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b) andR³ are optionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from methyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 1 group selected from C1-C4 alkyl, Ar⁴,and —C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b)and R³ are optionally covalently bonded together and, together with theintermediate atoms, comprise a oxazolidinyl substituted with 1 groupselected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, t-butyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet a furtheraspect, each of R^(1b) and R³ are optionally covalently bonded togetherand, together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, n-propyl,isopropyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an even further aspect,each of R^(1b) and R³ are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b) andR³ are optionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 1 groupselected from methyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1b) and R³ are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 1 group selected from C1-C4alkyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, eachof R^(1b) and R³ are optionally covalently bonded together and, togetherwith the intermediate atoms, comprise a 6-membered heterocycloalkylsubstituted with 1 group selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b) and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, n-propyl, isopropyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of Rib and R³are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, ethyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b) andR³ are optionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from methyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect,each of R^(1b′) and R^(3′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise a5-membered heterocycloalkyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted5-membered heterocycloalkyl.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet afurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise an oxazolidinyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of R andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an unsubstituted oxazolidinyl.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect,each of R^(1b′) and R^(3′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise a6-membered heterocycloalkyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R²³)Ar⁴. In an even further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an unsubstituted6-membered heterocycloalkyl.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5-membered heterocycloalkyl substitutedwith 1 group selected from C1-C4 alkyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 5-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,n-propyl, isopropyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an evenfurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, ethyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise an oxazolidinyl substituted with 1 groupselected from C1-C4 alkyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a stillfurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a oxazolidinyl substituted with 1 group selected from methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴,and —C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b′)and R^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, ethyl, n-propyl,isopropyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an even further aspect,each of R^(1b′) and R^(3′), when present, are optionally covalentlybonded together and, together with the intermediate atoms, comprise anoxazolidinyl substituted with 1 group selected from methyl, ethyl, Ar⁴,and —C(R^(203a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′)and R^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise an oxazolidinylsubstituted with 1 group selected from methyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 6-membered heterocycloalkyl substitutedwith 1 group selected from C1-C4 alkyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In yet a further aspect, each of R^(1b′) andR^(3′), when present, are optionally covalently bonded together and,together with the intermediate atoms, comprise a 6-memberedheterocycloalkyl substituted with 1 group selected from methyl, ethyl,n-propyl, isopropyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an evenfurther aspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 6-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, ethyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In a still furtheraspect, each of R^(1b′) and R^(3′), when present, are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 6-membered heterocycloalkyl substituted with 1 group selectedfrom methyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R^(1a), R^(1b), R^(1a′), and R^(1b′), whenpresent, is the same. In a still further aspect, each of R^(1a), R^(1b),R^(1a′), and R^(1b), when present, is Ar¹. In yet a further aspect, eachof R^(1a), R^(1b), R^(1a′), and R^(1b), when present, is phenyl. In aneven further aspect, each of R^(1a), R^(1b), R^(1a′), and R^(1b′), whenpresent, is unsubstituted phenyl. In a further aspect, each of R^(1a),R^(1b), R^(1a′), and R^(1b′), when present, is hydrogen. In a stillfurther aspect, each of R^(1a), R^(1b), R^(1a′), and R^(1b), whenpresent, is different.

b. R², R³, R^(2′), and R^(3′) Groups

In one aspect, each of R², R³, R^(2′), and R^(3′), when present, areindependently selected from —Si(R^(20a))(R^(20b))R^(20c), Ar², and—C(R^(21a))(R^(21b))Ar².

In a further aspect, each of R² and R³ are independently selected from—Si(R^(20a))(R^(20b))R^(20c), Ar², and —C(R^(21a))(R^(21b))Ar².

In a further aspect, each of R² and R³ are the same. In a still furtheraspect, each of R² and R³ are —Si(R^(20a))(R^(20b))R^(20c). In yet afurther aspect, each of R² and R³ are Ar². In an even further aspect,each of R² and R³ are —C(R^(21a))(R^(21b))Ar². In a still furtheraspect, each of R² and R³ are different.

In a further aspect, each of R² and R³ are independently—Si(R^(20a))(R^(20b))R^(20c). In a still further aspect, each of R² andR³ are —Si(Ph)₃.

In a further aspect, each of R² and R³ are independently selected fromAr² and —C(R^(21a))(R^(21b))Ar².

In a further aspect, each of R² and R³ are independently Ar². In a stillfurther aspect, each of R² and R³ are phenyl.

In a further aspect, each of R² and R³ are independently—C(R^(21a))(R^(21b))Ar². In a still further aspect, each of R² and R³are independently —CH(R^(21b))Ar². In yet a further aspect, each of R²and R³ are independently —CH(CH₃)Ar². In an even further aspect, each ofR² and R³ are independently —CH₂Ar².

In a further aspect, each of R² and R^(3′), when present, areindependently selected from —Si(R^(20a))(R^(20b))R^(20c), Ar², and—C(R^(21a))(R^(21b))Ar².

In a further aspect, each of R² and R^(3′), when present, are the same.In a still further aspect, each of R² and R³ are—Si(R^(20a))(R^(20b))R^(20c). In yet a further aspect, each of R² andR^(3′), when present, are Ar². In an even further aspect, each of R² andR^(3′), when present, are —C(R^(21a))(R^(21b))Ar². In a still furtheraspect, each of R² and R^(3′), when present, are different.

In a further aspect, each of R² and R^(3′), when present, areindependently —Si(R^(20a))(R^(20b))R^(20c). In a still further aspect,each of R^(2′) and R^(3′), when present, are —Si(Ph)₃.

In a further aspect, each of R² and R^(3′), when present, areindependently selected from Ar² and —C(R^(21a))(R^(21b))Ar².

In a further aspect, each of R² and R³, when present, are independentlyAr². In a still further aspect, each of R² and R^(3′), when present, arephenyl.

In a further aspect, each of R² and R^(3′), when present, areindependently —C(R^(21a))(R^(21b))Ar². In a still further aspect, eachof R² and R³, when present, are independently —CH(R^(21b))Ar². In yet afurther aspect, each of R² and R^(3′), when present, are independently—CH(CH₃)Ar². In an even further aspect, each of R² and R^(3′), whenpresent, are independently —CH₂Ar².

In a further aspect, each occurrence of R², and R³ is independently astructure selected from:

In a further aspect, each occurrence of R² and R³ is simultaneously astructure selected from:

In a further aspect, each occurrence of R² and R³ is independently astructure selected from:

In a further aspect, each occurrence of R² and R³ is simultaneously astructure selected from:

In a further aspect, each occurrence of R², R^(2′), R³, and R^(3′) isindependently a structure selected from:

In a further aspect, each occurrence of R², R^(2′), R³, and R^(3′) issimultaneously a structure selected from:

c. R⁴ Groups

In one aspect, R⁴, when present, is selected from —OH and —NHR²⁴. In astill further aspect, R⁴, when present, is —OH. In yet a further aspect,R⁴, when present, is —NHR²⁴. In an even further aspect, R⁴, whenpresent, is —NHTf.

d. R^(20A), R^(20B), and R^(20C) Groups

In one aspect, each occurrence of R², R^(20b), and R^(20c), whenpresent, is independently selected from C1-C4 alkyl and phenyl.

In a further aspect, each occurrence of R^(20a), R^(20b), and R^(20c),when present, is independently selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and phenyl. In a stillfurther aspect, each occurrence of R^(20a), R^(20b), and R^(20c), whenpresent, is independently selected from methyl, ethyl, n-propyl,isopropyl, and phenyl. In yet a further aspect, each occurrence ofR^(20a), R^(20b), and R^(20c), when present, is independently selectedfrom methyl, ethyl, and phenyl. In an even further aspect, eachoccurrence of R^(102a)R^(20b), and R^(20c), when present, isindependently selected from ethyl and phenyl. In a still further aspect,each occurrence of R^(20a), R^(20b) and R^(20c), when present, isindependently selected from methyl and phenyl.

In a further aspect, each occurrence of R^(20a), R^(20b), and R^(20c),when present, is independently selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, each occurrence of R^(20a), R^(20b), and R^(20c), when present,is independently selected from methyl, ethyl, n-propyl, and isopropyl.In yet a further aspect, each occurrence of R^(20a), R^(20b), andR^(20c), when present, is independently selected from methyl and ethyl.In an even further aspect, each occurrence of R^(20a), R^(20b), andR^(20c), when present, is ethyl. In a still further aspect, eachoccurrence of R^(20a), R^(20b), and R^(20c), when present, is methyl.

In a further aspect, each occurrence of R^(20a), R^(20b), and R^(20c),when present, is the same. In a still further aspect, each occurrence ofR^(20a), R^(20b), and R^(20c), when present, is phenyl. In yet a furtheraspect, each occurrence of R^(20a), R^(20b), and R^(20c), when present,is different.

e. R^(21A) and R^(21B) Groups

In one aspect, each occurrence of R^(21a) and R^(21b), when present, isindependently selected from hydrogen and C1-C4 alkyl. In a furtheraspect, each occurrence of R^(21a) and R²¹, when present, is hydrogen.

In a further aspect, each occurrence of R^(21a) and R^(21b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In astill further aspect, each occurrence of R^(21a) and R^(21b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, and isopropyl. In yet a further aspect, each occurrence ofR^(21a) and R^(21b), when present, is independently selected fromhydrogen, methyl, and ethyl. In an even further aspect, each occurrenceof R^(21a) and R^(21b), when present, is independently selected fromhydrogen and ethyl. In a still further aspect, each occurrence ofR^(21a) and R^(21b), when present, is independently selected fromhydrogen and methyl.

In a further aspect, each occurrence of R^(21a) and R^(21b), whenpresent, is independently selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, each occurrence of R^(21a) and R^(21b), when present, isindependently selected from methyl, ethyl, n-propyl, and isopropyl. Inyet a further aspect, each occurrence of R^(21a) and R^(21b), whenpresent, is independently selected from methyl, and ethyl. In an evenfurther aspect, each occurrence of R^(21a) and R^(21b), when present, isethyl. In a still further aspect, each occurrence of R^(21a) andR^(21b), when present, is methyl.

In a further aspect, each occurrence of R^(21a), when present, ishydrogen and each occurrence of R^(21b), when present, is independentlyC1-C4 alkyl. In a still further aspect, each occurrence of R^(21a), whenpresent, is hydrogen and each occurrence of R^(21b), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl. In yet a further aspect, eachoccurrence of R^(21a), when present, is hydrogen and each occurrence ofR^(21b), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In an even further aspect, each occurrence ofR^(21a), when present, is hydrogen and each occurrence of R^(21b), whenpresent, is independently selected from methyl and ethyl. In a stillfurther aspect, each occurrence of R^(21a), when present, is hydrogenand each occurrence of R^(21b), when present, is ethyl. In yet a furtheraspect, each occurrence of R^(21a) when present, is hydrogen and eachoccurrence of R^(21a), when present, is t-butyl. In an even furtheraspect, each occurrence of R^(21a), when present, is hydrogen and eachoccurrence of R²¹, when present, is methyl.

In a further aspect, each occurrence of R^(21a), when present, is thesame. In a still further aspect, each occurrence of R^(21a), whenpresent, is different.

In a further aspect, each occurrence of R^(21b), when present, is thesame. In a still further aspect, each occurrence of R^(21b), whenpresent, is different.

f. R^(22a) and R^(22B) Groups

In one aspect, each occurrence of R^(22a) and R^(22b), when present, isindependently selected from hydrogen and C1-C4 alkyl. In a furtheraspect, each occurrence of R^(22a) and R^(22b), when present, ishydrogen.

In a further aspect, each occurrence of R^(22a) and R^(22b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In astill further aspect, each occurrence of R^(22a) and R^(22b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, and isopropyl. In yet a further aspect, each occurrence ofR^(22a) and R^(22b), when present, is independently selected fromhydrogen, methyl, and ethyl. In an even further aspect, each occurrenceof R^(22a) and R^(22b), when present, is independently selected fromhydrogen and ethyl. In a still further aspect, each occurrence ofR^(22a) and R²², when present, is independently selected from hydrogenand methyl.

In a further aspect, each occurrence of R^(22a) and R^(22b), whenpresent, is independently selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, each occurrence of R^(22a) and R^(22b), when present, isindependently selected from methyl, ethyl, n-propyl, and isopropyl. Inyet a further aspect, each occurrence of R^(22a) and R^(22b), whenpresent, is independently selected from methyl, and ethyl. In an evenfurther aspect, each occurrence of R^(22a) and R^(22b), when present, isethyl. In a still further aspect, each occurrence of R^(22a) andR^(22b), when present, is methyl.

In a further aspect, each occurrence of R^(22a), when present, ishydrogen and each occurrence of R^(22b), when present, is independentlyC1-C4 alkyl. In a still further aspect, each occurrence of R^(22a), whenpresent, is hydrogen and each occurrence of R^(22b), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl. In yet a further aspect, eachoccurrence of R^(22a), when present, is hydrogen and each occurrence ofR^(22b), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In an even further aspect, each occurrence ofR^(22a), when present, is hydrogen and each occurrence of R^(22b), whenpresent, is independently selected from methyl and ethyl. In a stillfurther aspect, each occurrence of R^(22a), when present, is hydrogenand each occurrence of R^(22b), when present, is ethyl. In yet a furtheraspect, each occurrence of R^(22a), when present, is hydrogen and eachoccurrence of R^(22b), when present, is t-butyl. In an even furtheraspect, each occurrence of R^(22a), when present, is hydrogen and eachoccurrence of R^(22b), when present, is methyl.

In a further aspect, each occurrence of R^(22a), when present, is thesame. In a still further aspect, each occurrence of R^(22a), whenpresent, is different.

In a further aspect, each occurrence of R^(22b), when present, is thesame. In a still further aspect, each occurrence of R^(22b), whenpresent, is different.

g. R^(23A) and R^(23B) Groups

In one aspect, each occurrence of R^(23a) and R^(23b), when present, isindependently selected from hydrogen and C1-C4 alkyl. In a furtheraspect, each occurrence of R^(23a) and R^(23b), when present, ishydrogen.

In a further aspect, each occurrence of R^(23a) and R^(23b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In astill further aspect, each occurrence of R^(23a) and R^(23b), whenpresent, is independently selected from hydrogen, methyl, ethyl,n-propyl, and isopropyl. In yet a further aspect, each occurrence ofR^(23a) and R^(23b), when present, is independently selected fromhydrogen, methyl, and ethyl. In an even further aspect, each occurrenceof R^(23a) and R^(23b), when present, is independently selected fromhydrogen and ethyl. In a still further aspect, each occurrence ofR^(23a) and R^(23b), when present, is independently selected fromhydrogen and methyl.

In a further aspect, each occurrence of R^(23a) and R^(23b), whenpresent, is independently selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, each occurrence of R^(23a) and R^(23b), when present, isindependently selected from methyl, ethyl, n-propyl, and isopropyl. Inyet a further aspect, each occurrence of R^(23a) and R^(23b), whenpresent, is independently selected from methyl, and ethyl. In an evenfurther aspect, each occurrence of R^(23a) and R^(23b), when present, isethyl. In a still further aspect, each occurrence of R^(23a) andR^(23b), when present, is methyl.

In a further aspect, each occurrence of R^(23a), when present, ishydrogen and each occurrence of R^(23b), when present, is independentlyC1-C4 alkyl. In a still further aspect, each occurrence of R^(23a), whenpresent, is hydrogen and each occurrence of R^(23b), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl. In yet a further aspect, eachoccurrence of R^(23a), when present, is hydrogen and each occurrence ofR^(23b), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In an even further aspect, each occurrence ofR^(23a), when present, is hydrogen and each occurrence of R^(23b), whenpresent, is independently selected from methyl and ethyl. In a stillfurther aspect, each occurrence of R^(23a), when present, is hydrogenand each occurrence of R^(23b), when present, is ethyl. In yet a furtheraspect, each occurrence of R^(203a), when present, is hydrogen and eachoccurrence of R^(23b), when present, is t-butyl. In an even furtheraspect, each occurrence of R^(23a), when present, is hydrogen and eachoccurrence of R^(23b), when present, is methyl.

In a further aspect, each occurrence of R^(23a), when present, is thesame. In a still further aspect, each occurrence of R^(23a), whenpresent, is different.

In a further aspect, each occurrence of R^(23b), when present, is thesame. In a still further aspect, each occurrence of R^(23b), whenpresent, is different.

h. R²⁴ Groups

In one aspect, R²⁴, when present, is an amine protecting group. Examplesof amine protecting groups include, but are not limited to,carboxybenzyl (Cbz), t-butoxycarbonyl (Boc),9-fluorenylmethyloxycarbonyl (Fmoc), acetyl, benzoyl (Bz), benzyl (Bn),para-methoxybenzyl (PMB), tosyl (Ts), and triflate (Tf). In a furtheraspect, R²⁴ is triflate.

i. R³¹ and R^(31′) Groups

In one aspect, R³¹ is selected from C1-C4 alkyl, Ar³, and—C(R^(22a))(R^(22b))Ar³.

In one aspect, each of R³¹ and R^(31′), when present, is independentlyselected from C1-C4 alkyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, R³¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, R³¹ is selected frommethyl, ethyl, n-propyl, isopropyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. Inyet a further aspect, R³¹ is selected from methyl, ethyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In an even further aspect, R³¹ is selected frommethyl, Ar³, and —C(R^(22a))(R^(22b))Ar³.

In a further aspect, R³ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, R³¹ is selected from methyl, ethyl, n-propyl, and isopropyl. Inyet a further aspect, R³¹ is selected from methyl and ethyl. In an evenfurther aspect, R³¹ is ethyl. In a still further aspect, R³¹ is methyl.

In a further aspect, R³¹ is selected from Ar³ and—C(R^(22a))(R^(22b))Ar³. In a still further aspect, R³¹ is Ar³. In yet afurther aspect, R³¹ is —C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R³¹ and R^(31′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, Ar³, and —C(R^(22a))(R^(22b))Ar³. In astill further aspect, each of R³¹ and R^(31′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, Ar³, and—C(R^(22a))(R^(22b))Ar³. In yet a further aspect, each of R³¹ andR^(31′), when present, is independently selected from methyl, ethyl,Ar³, and —C(R^(22a))(R^(22b))Ar³. In an even further aspect, each of R³¹and R^(31′), when present, is independently selected from methyl, Ar³,and C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R³¹ and R^(31′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl. In a still further aspect, each of R³¹and R^(31′), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In yet a further aspect, each of R³¹ andR^(31′), when present, is independently selected from methyl and ethyl.In an even further aspect, each of R³¹ and R^(31′), when present, isethyl. In a still further aspect, each of R³¹ and R^(31′), when present,is methyl.

In a further aspect, each of R³¹ and R^(31′), when present, isindependently selected from Ar³ and —C(R^(22a))(R^(22b))Ar³. In a stillfurther aspect, each of R³¹ and R^(31′), when present, is Ar³. In yet afurther aspect, each of R³¹ and R^(31′), when present, is—C(R^(22a))(R^(22b))Ar³.

In a further aspect, each of R³¹ and R^(31′), when present, is the same.In a still further aspect, each of R³¹ and R^(31′), when present, isdifferent.

In a further aspect, each occurrence of R³¹, R^(31′), R³², and R^(32′)is simultaneously selected from methyl, isopropyl, t-butyl, phenyl, andbenzyl. In a still further aspect, each occurrence of R³¹, R^(31′), R³²,and R^(32′) is independently selected from methyl, isopropyl, t-butyl,phenyl, and benzyl.

In a further aspect, each of R³¹ and R^(31′), when present, are the sameand each of R³² and R^(32′), when present, are the same. In a stillfurther aspect, each of R³¹, R^(31′), R³², and R^(32′) are the same. Inyet a further aspect, each of R³¹, R^(31′), R³², and R^(32′) aredifferent.

j. R³² and R^(32′) Groups

In one aspect, R³² is selected from C1-C4 alkyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴.

In one aspect, each of R³² and R^(32′), when present, is independentlyselected from C1-C4 alkyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, R³² is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, R³² is selected frommethyl, ethyl, n-propyl, isopropyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. Inyet a further aspect, R³² is selected from methyl, ethyl, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, R³² is selected frommethyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, R³² is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. In a still furtheraspect, R³² is selected from methyl, ethyl, n-propyl, and isopropyl. Inyet a further aspect, R³² is selected from methyl and ethyl. In an evenfurther aspect, R³² is ethyl. In a still further aspect, R³² is ethyl.

In a further aspect, R³² is selected from Ar⁴ and—C(R^(23a))(R^(23b))Ar⁴. In a still further aspect, R³² is Ar⁴. In yet afurther aspect, R³² is —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R³² and R^(32′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, t-butyl, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In astill further aspect, each of R³² and R^(32′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, Ar⁴, and—C(R^(203a))(R^(23b))Ar⁴. In yet a further aspect, each of R³² andR^(32′), when present, is independently selected from methyl, ethyl,Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴. In an even further aspect, each of R³²and R^(32′) when present, is independently selected from methyl, Ar⁴,and —C(R^(23a))(R^(23b))Ar⁴.

In a further aspect, each of R³² and R^(32′), when present, isindependently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and t-butyl. In a still further aspect, each of R³²and R^(32′), when present, is independently selected from methyl, ethyl,n-propyl, and isopropyl. In yet a further aspect, each of R³² andR^(32′), when present, is independently selected from methyl and ethyl.In an even further aspect, each of R³² and R^(32′) when present, isethyl. In a still further aspect, each of R³² and R^(32′), when present,is ethyl.

In a further aspect, each of R³² and R^(32′), when present, isindependently selected from Ar⁴ and —C(R^(23a))(R^(23b))Ar⁴. In a stillfurther aspect, each of R³² and R^(32′), when present, is Ar⁴. In yet afurther aspect, each of R³² and R^(32′), when present, is—C(R^(203a))(R^(23b))Ar⁴.

In a further aspect, each of R³² and R^(32′), when present, is the same.In a still further aspect, each of R³² and R^(32′), when present, isdifferent.

k. R³³, R^(33′), R³⁴, and R^(34′) Groups

In one aspect, each occurrence of R³³, R^(33′), R³⁴, and R^(34′) issimultaneously a structure selected from:

In a further aspect, each occurrence of R³³, R^(33′), R³⁴, and R^(34′)is independently a structure selected from:

l. Ar¹ Groups

In one aspect, each occurrence of Ar¹, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In afurther aspect, each occurrence of Ar¹, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar¹, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each occurrence of Ar¹, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar¹, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, isindependently 4-10 membered heteroaryl, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar¹, when present, is independently 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar¹, when present, is independently 4-10 memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar¹, when present, is independently 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar¹, when present, is independently 4-10 memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, isindependently 6-membered heteroaryl, and is substituted with 0, 1, 2, or3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar¹, when present, is independently 6-membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar¹, when present, is independently 6-memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar¹, when present, is independently 6-memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar¹, when present, is independently 6-memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, isindependently pyridinyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently pyridinyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr¹, when present, is independently pyridinyl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar¹, whenpresent, is independently pyridinyl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently pyridinyl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, isindependently C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently C6-C14 aryl, and is substituted with 0, 1, or2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr¹, when present, is independently C6-C14 aryl, and is substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar¹, whenpresent, is independently C6-C14 aryl, and is monosubstituted with agroup selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently C6-C14 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, isindependently C6 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently C6 aryl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr¹, when present, is independently C6 aryl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar¹, whenpresent, is independently C6 aryl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar¹, whenpresent, is independently C6 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar¹, when present, is the same.In a still further aspect, each occurrence of Ar¹, when present, isunsubstituted C6 aryl. In yet a further aspect, each occurrence of Ar¹,when present, is different.

m. Ar² Groups

In one aspect, each occurrence of Ar², when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In a further aspect, each occurrence of Ar², when present, isindependently selected from C6-C14 aryl and 4-10 membered heteroaryl,and is substituted with 0, 1, or 2 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In a still further aspect, each occurrence of Ar², when present, isindependently selected from C6-C14 aryl and 4-10 membered heteroaryl,and is substituted with 0 or 1 group selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a furtheraspect, each occurrence of Ar², when present, is independently selectedfrom C6-C14 aryl and 4-10 membered heteroaryl, and is monosubstitutedwith a group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In an even further aspect, each occurrence ofAr², when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently 4-10 membered heteroaryl, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently 4-10 memberedheteroaryl, and is substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In yet a further aspect, each occurrence ofAr², when present, is independently 4-10 membered heteroaryl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, each occurrence of Ar², when present, is independently 4-10membered heteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently 6-membered heteroaryl, and is substituted with 0, 1, 2, or3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently 6-membered heteroaryl,and is substituted with 0, 1, or 2 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In yet a further aspect, each occurrence of Ar², when present, isindependently 6-membered heteroaryl, and is substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In an even further aspect, each occurrence ofAr², when present, is independently 6-membered heteroaryl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently 6-membered heteroaryl,and is unsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently pyridinyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, each occurrence ofAr², when present, is independently pyridinyl, and is substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, eachoccurrence of Ar², when present, is independently pyridinyl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently pyridinyl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently pyridinyl, and isunsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, each occurrence ofAr², when present, is independently C6-C14 aryl, and is substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, eachoccurrence of Ar², when present, is independently C6-C14 aryl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently C6-C14 aryl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently C6-C14 aryl, and isunsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently C6 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, each occurrence ofAr², when present, is independently C6 aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, eachoccurrence of Ar², when present, is independently C6 aryl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently C6 aryl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently C6 aryl, and isunsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently C10 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, each occurrence ofAr², when present, is independently C10 aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, eachoccurrence of Ar², when present, is independently C10 aryl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently C10 aryl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently C10 aryl, and isunsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently C14 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, each occurrence ofAr², when present, is independently C14 aryl, and is substituted with 0,1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, eachoccurrence of Ar², when present, is independently C14 aryl, and issubstituted with 0 or 1 group selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In an even further aspect, eachoccurrence of Ar², when present, is independently C14 aryl, and ismonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect, eachoccurrence of Ar², when present, is independently C14 aryl, and isunsubstituted.

In a further aspect, each occurrence of Ar², when present, isindependently C6 aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, C1-C4 alkyl, and phenyl. In astill further aspect, each occurrence of Ar², when present, isindependently C6 aryl substituted with 0, 1, or 2 groups independentlyselected from halogen, —NO₂, C1-C4 alkyl, and phenyl. In yet a furtheraspect, each occurrence of Ar², when present, is independently C6 arylsubstituted with 0 or 1 group selected from halogen, —NO₂, C1-C4 alkyl,and phenyl. In an even further aspect, each occurrence of Ar², whenpresent, is independently C6 aryl monosubstituted with a group selectedfrom halogen, —NO₂, C1-C4 alkyl, and phenyl.

In a further aspect, each occurrence of Ar², when present, is the same.In a still further aspect, each occurrence of Ar², when present, isdifferent.

n. Ar³ Groups

In one aspect, each occurrence of Ar³, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In afurther aspect, each occurrence of Ar³, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar³, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each occurrence of Ar³, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar³, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, isindependently 4-10 membered heteroaryl, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar³, when present, is independently 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar³, when present, is independently 4-10 memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar³, when present, is independently 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar³, when present, is independently 4-10 memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, isindependently 6-membered heteroaryl, and is substituted with 0, 1, 2, or3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar³, when present, is independently 6-membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar³, when present, is independently 6-memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar³, when present, is independently 6-memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar³, when present, is independently 6-memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, isindependently pyridinyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently pyridinyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr³, when present, is independently pyridinyl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar³, whenpresent, is independently pyridinyl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently pyridinyl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, isindependently C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently C6-C14 aryl, and is substituted with 0, 1, or2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr³, when present, is independently C6-C14 aryl, and is substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar³, whenpresent, is independently C6-C14 aryl, and is monosubstituted with agroup selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently C6-C14 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, isindependently C6 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently C6 aryl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr³, when present, is independently C6 aryl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar³, whenpresent, is independently C6 aryl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar³, whenpresent, is independently C6 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar³, when present, is the same.In a still further aspect, each occurrence of Ar³, when present, isunsubstituted C6 aryl. In yet a further aspect, each occurrence of Ar³,when present, is different.

o. Ar⁴ Groups

In one aspect, each occurrence of Ar⁴, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In afurther aspect, each occurrence of Ar⁴, when present, is independentlyselected from C6-C14 aryl and 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar⁴, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, each occurrence of Ar⁴, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar⁴, when present, is independently selected fromC6-C14 aryl and 4-10 membered heteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, isindependently 4-10 membered heteroaryl, and is substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar⁴, when present, is independently 4-10 membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar⁴, when present, is independently 4-10 memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar⁴, when present, is independently 4-10 memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar⁴, when present, is independently 4-10 memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, isindependently 6-membered heteroaryl, and is substituted with 0, 1, 2, or3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each occurrenceof Ar⁴, when present, is independently 6-membered heteroaryl, and issubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,each occurrence of Ar⁴, when present, is independently 6-memberedheteroaryl, and is substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,each occurrence of Ar⁴, when present, is independently 6-memberedheteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,each occurrence of Ar⁴, when present, is independently 6-memberedheteroaryl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, isindependently pyridinyl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently pyridinyl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr⁴, when present, is independently pyridinyl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar⁴, whenpresent, is independently pyridinyl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently pyridinyl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, isindependently C6-C14 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently C6-C14 aryl, and is substituted with 0, 1, or2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr⁴, when present, is independently C6-C14 aryl, and is substituted with0 or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar⁴, whenpresent, is independently C6-C14 aryl, and is monosubstituted with agroup selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently C6-C14 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, isindependently C6 aryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently C6 aryl, and is substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, each occurrence ofAr⁴, when present, is independently C6 aryl, and is substituted with 0or 1 group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each occurrence of Ar⁴, whenpresent, is independently C6 aryl, and is monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, each occurrence of Ar⁴, whenpresent, is independently C6 aryl, and is unsubstituted.

In a further aspect, each occurrence of Ar⁴, when present, is the same.In a still further aspect, each occurrence of Ar⁴, when present, isunsubstituted C6 aryl. In yet a further aspect, each occurrence of Ar⁴,when present, is different.

2. N-Heterocyclic Phosphorodiamidic Acid Examples

In one aspect, a compound is selected from:

or a salt thereof.

In one aspect, a compound is selected from:

or a salt thereof.

3. Prophetic Compound Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. It is anticipatedthat the prophetic compounds would be useful in the generation ofortho-quinone methides leading to the preparation of diaryl andarylalkyl phosphonates, and such utility can be determined using thesynthetic methods described herein below.

In one aspect, a compound can be selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

wherein each occurrence of R², R^(2′), R³, and R^(3′) is simultaneouslya structure selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

wherein each occurrence of R³³, R^(33′), R³⁴, and R^(34′) issimultaneously a structure selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

wherein each occurrence of R³¹, R^(31′), R³², and R^(32′) issimultaneously selected from methyl, isopropyl, t-butyl, phenyl, andbenzyl, or a salt thereof.

In one aspect, a compound can be selected from:

or a salt thereof.

C. Diaryl and Arylalkyl Phosphonates

In one aspect, the invention relates to diaryl and arylalkylphosphonates useful in, for example, the synthesis of leukocyte elastasinhibitors, potassium channel modulators, chemiluminescence materials,and flame retardants. The use of the disclosed diaryl and arylalkylphosphonates in the synthesis of other pharmaceutically active compoundsis also envisioned.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein n is selected from 0 and 1; wherein each of R^(101a) andR^(101b) is independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino, provided that at least oneof R^(101a) and R¹⁰¹¹ is —OH, —SH, or C1-C4 alkylamino; wherein each ofR^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein R¹⁰³ is selected from C4-C8 alkyl and Ar¹⁰¹,provided that when R¹⁰³ is C4-C8 alkyl, then either: (a) at least one ofR^(101a) and R^(101b) is —SH or C1-C4 alkylamino, or (b) then R^(101b)is —OH; wherein Ar¹⁰¹, when present, is selected from C6-C10 aryl andC5-C6 heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl; wherein R¹⁰⁴ is selected from C1-C4 alkoxy andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; andwherein R¹⁰⁵ is C1-C4 alkyl, provided that when n is 0, R^(101a) is —OH,R¹⁰³ is C6 aryl, R¹⁰⁴ is ethoxy, and R¹⁰⁵ is ethyl, then either: (c) atleast two of R^(101a), R^(102a), R^(102b), and R^(102c) are nothydrogen, (d) R¹⁰³ is substituted with 2 or 3 groups, or (e) at leastone of R¹⁰¹, R^(201a), R^(102b), and R^(102c) is not hydrogen and R¹⁰³is substituted with 1, 2, or 3 groups; and provided that when n is 0,R^(101b) is —OH, and R¹⁰³ is C6 aryl or C6 heteroaryl, then either: (f)each of R^(12a) and R^(102b) is hydrogen; or (g) one of R^(102a) andR^(102b) is hydrogen and R¹⁰⁴ is not the same as —OR⁵, or apharmaceutically acceptable salt thereof.

Also disclosed are compounds selected from:

or a pharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(120a), R^(120b), R^(120c), R^(120d), and R^(120e) areindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl.

In a further aspect, the compound has a structure represented by aformula:

wherein each of R^(130a), R^(130b), R^(130c), R^(130d), and R^(130e) areindependently selected from hydrogen, halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino.

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, the compound has a structure represented by aformula selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, n is selected from 0 and 1. In a still furtheraspect, n is 0. In yet a further aspect, n is 1.

In a further aspect, when n is 0, R^(101a) is —OH, R¹⁰³ is C6 aryl, R¹⁰⁴is ethoxy, and R¹⁰⁵ is ethyl then at least two of R^(101b), R^(102a),R^(102b), and R^(102c) are not hydrogen.

In a further aspect, when n is 0, R^(101a) is —OH, R¹⁰³ is C6 aryl, R¹⁰⁴is ethoxy, and R¹⁰⁵ is ethyl then R¹⁰³ is substituted with 2 or 3groups.

In a further aspect, n is 0, R^(101a) is —OH, R¹⁰³ is C6 aryl, R¹⁰⁴ isethoxy, and R¹⁰⁵ is ethyl then at least one of R^(101b), R^(201a),R^(102b), and R^(102c) is not hydrogen and R¹⁰³ is substituted with 1,2, or 3 groups.

In a further aspect, when n is 0, R^(101b) is —OH, and R¹⁰³ is C6 arylor C6 heteroaryl, then each of R^(102a) and R^(102b) is hydrogen.

In a further aspect, when n is 0, R^(101b) is —OH, and R¹⁰³ is C6 arylor C6 heteroaryl, then one of R^(102a) and R^(102b) is hydrogen and R¹⁰⁴is not the same as —OR.

a. R^(101A) and R^(101B) Groups

In one aspect, each of R^(101a) and R^(101b) is independently selectedfrom hydrogen, halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino, provided that at least one of R^(101a) and R^(101b) is—OH, —SH, or C1-C4 alkylamino.

In a further aspect, each of R^(101a) and R^(101b) is independentlyselected from hydrogen, —F, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl,ethyl, n-propyl, isopropyl, ethyenyl, propenyl, ethynyl, propynyl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂,—CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN,—CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —CH₂OCF₃, —CH₂CH₂OCF₃, —CH₂CH₂CH₂OCF₃, —CH(CH₃)CH₂OCF₃,—CH₂OCH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃, —CH(CH₃)CH₂OCH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,—CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,and —N(CH₃)CH₂CH₃. In a still further aspect, each of R^(101a) andR^(101b) is independently selected from hydrogen, —F, —Cl, —NO₂, —CN,—OH, —SH, —NH₂, methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂OCF₃, —CH₂CH₂OCF₃, —CH₂OCH₃, —CH₂CH₂OCH₃, —SCH₃,—SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, and —N(CH₂CH₃)₂. In yet a further aspect, each of R^(101a) andR^(101b) is independently selected from hydrogen, —F, —Cl, —NO₂, —CN,—OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CN, —CH₂OH, —CH₂OCF₃, —CH₂OCH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂,—NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(101a) and R^(1b) is independentlyselected from hydrogen, —OH, —SH, and C1-C4 alkylamino. In a stillfurther aspect, each of R^(101a) and R^(101b) is independently selectedfrom hydrogen, —OH, —SH, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHC(CH₃)₂,—NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. In yet a further aspect, each ofR^(101a) and R^(101b) is independently selected from hydrogen, —OH, —SH,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even furtheraspect, each of R^(101a) and R^(101b) is independently selected fromhydrogen, —OH, —SH, —NHCH₃, and —NHCH₂CH₃. In a still further aspect,each of R^(101a) and R^(101b) is independently selected from hydrogen,—OH, —SH, and —NHCH₃.

In a further aspect, one of R^(101a) and R^(101b) is —OH. In a furtheraspect, one of R^(101a) and R^(101b) is —SH. In a still further aspect,one of R^(101a) and R^(101b) is C1-C4 alkylamino. In yet a furtheraspect, one of R^(101a) and R^(101b) is —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, or —NHC(CH₃)₃. In an even further aspect,one of R^(101a) and R^(101b) is —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, or—NHC(CH₃)₂. In a still further aspect, one of R^(101a) and R^(101b) is—NHCH₃ or —NHCH₂CH₃. In yet a further aspect, one of R^(101a) andR^(101b) is —NHCH₂CH₃. In an even further aspect, one of R^(101a) andR^(101b) is —NHCH₃.

In a further aspect, one of R^(101a) and R^(101b) is hydrogen and one ofR^(101a) and R^(101b) is selected from —OH, —SH, and C1-C4 alkylamino.In a still further aspect, one of R^(101a) and R^(101b) is hydrogen andone of R^(101a) and R^(101b) is selected from —OH, —SH, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. Inyet a further aspect, one of R^(101a) and R^(101b) is hydrogen and oneof R^(101a) and R^(1b) is selected from —OH, —SH, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even further aspect, one of R^(101a)and R^(101b) is hydrogen and one of R^(101a) and R^(101b) is selectedfrom —OH, —SH, —NHCH₃, and —NHCH₂CH₃. In a still further aspect, one ofR^(101a) and R^(101b) is hydrogen and one of R^(101a) and R^(101b) isselected from —OH, —SH, and —NHCH₃.

In a further aspect, R^(101b) is hydrogen and R^(101a) is selected from—OH, —SH, and C1-C4 alkylamino. In a still further aspect, R^(101b) ishydrogen and R^(101a) is selected from —OH, —SH, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. In yet afurther aspect, R¹ is hydrogen and R^(101a) is selected from —OH, —SH,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even furtheraspect, R^(101b) is hydrogen and R^(101a) is selected from —OH, —SH,—NHCH₃, and —NHCH₂CH₃. In a still further aspect, R^(101b) is hydrogenand R^(101a) is selected from —OH, —SH, and —NHCH₃.

In a further aspect, R^(101a) is hydrogen and R^(101b) is selected from—OH, —SH, and C1-C4 alkylamino. In a still further aspect, R^(101a) ishydrogen and R^(1b) is selected from —OH, —SH, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. In yet afurther aspect, R^(101a) is hydrogen and R^(101b) is selected from —OH,—SH, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even furtheraspect, R^(101a) is hydrogen and R^(101b) is selected from —OH, —SH,—NHCH₃, and —NHCH₂CH₃. In a still further aspect, R^(101a) is hydrogenand R^(101b) is selected from —OH, —SH, and —NHCH₃.

In a further aspect, R^(101a) is selected from —OH, —SH, and C1-C4alkylamino. In a still further aspect, R^(101a) is selected from —OH,—SH, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and—NHC(CH₃)₃. In yet a further aspect, R^(101a) is selected from —OH, —SH,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even furtheraspect, R^(101a) is selected from —OH, —SH, —NHCH₃, and —NHCH₂CH₃. In astill further aspect, R^(101a) is selected from —OH, —SH, and —NHCH₃.

In a further aspect, R^(101a) is selected from —OH and —SH. In a furtheraspect, R^(101a) is —OH. In a still further aspect, R^(101a) is —SH.

In a further aspect, R^(101a) is C1-C4 alkylamino. In a still furtheraspect, R^(101a) is selected from —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. In yet a further aspect,R^(101a) is selected from —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and—NHC(CH₃)₂. In an even further aspect, R^(101a) is selected from —NHCH₃and —NHCH₂CH₃. In a still further aspect, R^(101a) is —NHCH₂CH₃. In yeta further aspect, R^(101a) is —NHCH₃.

In a further aspect, R^(101b) is selected from —OH, —SH, and C1-C4alkylamino. In a still further aspect, R^(101b) is selected from —OH,—SH, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and—NHC(CH₃)₃. In yet a further aspect, R^(101b) is selected from —OH, —SH,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and —NHC(CH₃)₂. In an even furtheraspect, R^(101b) is selected from —OH, —SH, —NHCH₃, and —NHCH₂CH₃. In astill further aspect, R^(101b) is selected from —OH, —SH, and —NHCH₃.

In a further aspect, R^(101b) is selected from —OH and —SH. In a furtheraspect, R^(101b) is —OH. In a still further aspect, R^(1b) is —SH.

In a further aspect, R^(101b) is C1-C4 alkylamino. In a still furtheraspect, R^(101b) is selected from —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHC(CH₃)₂, —NHCH₂CH₂CH₂CH₃, and —NHC(CH₃)₃. In yet a further aspect,R^(101b) is selected from —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, and—NHC(CH₃)₂. In an even further aspect, R^(101b) is selected from —NHCH₃and —NHCH₂CH₃. In a still further aspect, R^(101b) is —NHCH₂CH₃. In yeta further aspect, R^(101b) is —NHCH₃.

b. R^(102A), R^(102B), and R^(102c) Groups

In one aspect, each of R^(102a), R^(102b), and R^(102c) is independentlyselected from hydrogen, halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, each of R^(102a), R^(102b), andR^(102c) is hydrogen.

In a further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl, propenyl, ethynyl,propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂CN,—CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,—CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,and —N(CH₃)CH₂CH₃. In a still further aspect, each of R^(12a), R^(2b)and R^(102c) is independently selected from hydrogen, —F, —Br, —Cl,—NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethyenyl, ethynyl, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN,—CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃,—SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, and —N(CH₂CH₃)₂. In yet a further aspect, each ofR^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂,—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃,—SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, and —N(CH₃)₂.

In various aspects, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, halogen, —NO₂, —CN, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 haloalkoxy, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —F, —Br, —Cl, —NO₂,—CN, —NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl, propenyl,ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F,—CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂NH₂,—CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, and —N(CH₃)CH₂CH₃.In a still further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, —F, —Br, —Cl, —NO₂, —CN, —NH₂,methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl,—CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂NH₂, —CH₂CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, and —N(CH₂CH₃)₂. In yet a further aspect,each of R^(102a), R^(2b), and R^(12e) is independently selected fromhydrogen, —F, —Br, —Cl, —NO₂, —CN, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂NH₂, —NHCH₃, and —N(CH₃)₂.

In various aspects, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, halogen, —OH, —SH, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, and C1-C4 alkylthiol. In afurther aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, —F, —Br, —Cl, —OH, —SH, methyl,ethyl, n-propyl, isopropyl, ethyenyl, propenyl, ethynyl, propynyl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂,—CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂OH, —CH₂CH₂OH,—CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F,—OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃,—SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,and —CH(CH₃)CH₂SH. In a still further aspect, each of R^(102a),R^(102b), and R^(102c) is independently selected from hydrogen, —F, —Br,—Cl, —OH, —SH, methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂OH, —CH₂CH₂OH, —OCF₃,—OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, and—CH₂CH₂SH. In yet a further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —F, —Br, —Cl, —OH,—SH, methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH,—OCF₃, —OCH₂F, —OCH₃, —SCH₃, —SCH₂CH₃, and —CH₂SH.

In various aspects, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl, propenyl, ethynyl,propynyl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH,—CH₂CH₂CH₂SH, —CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,—CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, and —N(CH₃)CH₂CH₃. In a still further aspect,each of R^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethyenyl, ethynyl,—CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, and —N(CH₂CH₃)₂. In yet a further aspect,each of R^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂CN, —CH₂OH, —OCF₃,—OCH₂F, —OCH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, halogen, C1-C4 alkyl, and C1-C4alkoxy. In a still further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —F, —Br, —Cl, methyl,ethyl, n-propyl, isopropyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and—OCH(CH₃)CH₃. In yet a further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —F, —C1, methyl,ethyl, —OCH₃ and —OCH₂CH₃. In an even further aspect, each of R^(102a),R^(102b) and R^(102c) is independently selected from hydrogen, —F, —Br,—Cl, methyl, and —OCH₃.

In a further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen and halogen. In a still furtheraspect, each of R^(102a), R^(102b), and R^(102c) is independentlyselected from hydrogen, —F, —Br, and —Cl. In yet a further aspect, eachof R^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen and —F. In an even further aspect, each of R^(102a), R^(102b),and R^(102c) is independently selected from hydrogen and —Br. In a stillfurther aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen and —Cl.

In a further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen and C1-C4 alkyl. In a still furtheraspect, each of R^(102a), R^(102b), and R^(102c) is independentlyselected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and tert-butyl. In yet a further aspect, each ofR^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, each of R^(102a), R^(102b), and R^(102c) is independentlyselected from hydrogen, methyl, and ethyl. In yet a further aspect, eachof R^(102a), R^(102b), and R^(102c) is independently selected fromhydrogen and t-butyl. In an even further aspect, each of R^(102a),R^(102b), and R^(102c) is independently selected from hydrogen andethyl. In a still further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen and methyl.

In a further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen and C1-C4 alkoxy. In a stillfurther aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and—OCH(CH₃)CH₃. In yet a further aspect, each of R^(102a), R^(102b), andR^(102c) is independently selected from hydrogen, —OCH₃, and —OCH₂CH₃.In an even further aspect, each of R^(102a), R^(102b), and R^(102c) isindependently selected from hydrogen and —OCH₂CH₃. In a still furtheraspect, each of R^(102a), R^(102b), and R^(102c) is independentlyselected from hydrogen and —OCH₃.

In various aspects, R^(102a) is selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,and (C1-C4)(C1-C4) dialkylamino. In a further aspect, R^(102a) isselected from —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl,n-propyl, isopropyl, ethyenyl, propenyl, ethynyl, propynyl, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN,—CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃,—OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —CH(CH₃)CH₂OCH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,—CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,and —N(CH₃)CH₂CH₃. In a still further aspect, R^(102a) is selected from—F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethyenyl,ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, and —N(CH₂CH₃)₂. In yet a further aspect,R^(102a) is selected from —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂,methyl, —CH₂F, —CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH,—OCF₃, —OCH₂F, —OCH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, and—N(CH₃)₂.

In a further aspect, R^(101a) is C1-C4 alkyl. In a still further aspect,R^(102a) is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, and tert-butyl. In yet a further aspect, R^(102a)is selected from methyl, ethyl, n-propyl, and isopropyl. In a stillfurther aspect, R^(102a) is selected from methyl, and ethyl. In yet afurther aspect, R^(102a) is t-butyl. In an even further aspect, R^(102a)is ethyl. In a still further aspect, R^(102a) is methyl.

In a further aspect, R^(102a) is not hydrogen.

c. R¹⁰³ Groups

In one aspect, R¹⁰³ is selected from C4-C8 alkyl and Ar¹⁰¹, providedthat when R¹⁰³ is C4-C8 alkyl, then either (a) at least one of R^(101a)and R^(101b) is —SH or C1-C4 alkylamino, or (b) R^(101b) is —OH.

In a further aspect, when R¹⁰³ is C4-C8 alkyl, then at least one ofR^(101a) and R^(101b) is —SH or C1-C4 alkylamino. In a still furtheraspect, when R¹⁰³ is C4-C8 alkyl, then R^(101b) is —OH.

In a further aspect, R¹⁰³ is selected from C4-C7 alkyl and Ar¹⁰¹. In astill further aspect, R¹⁰³ is selected from C4-C6 alkyl and Ar¹⁰¹. Inyet a further aspect, R¹⁰³ is selected from C4-C5 alkyl and Ar¹⁰¹. In aneven further aspect, R¹⁰³ is selected from C8 alkyl and Ar¹⁰¹. In astill further aspect, R¹⁰³ is selected from C7 alkyl and Ar¹⁰¹. In yet afurther aspect, R¹⁰³ is selected from C6 alkyl and Ar¹⁰¹. In an evenfurther aspect, R¹⁰³ is selected from C5 alkyl and Ar¹⁰¹. In a stillfurther aspect, R¹⁰³ is selected from C4 alkyl and Ar¹⁰¹.

In a further aspect, R¹⁰³ is C4-C8 alkyl. In a still further aspect,R¹⁰³ is C4-C7 alkyl. In yet a further aspect, R¹⁰³ is C4-C6 alkyl. In aneven further aspect, R¹⁰³ is C4-C5 alkyl. In a still further aspect,R¹⁰³ is C8 alkyl. In yet a further aspect, R¹⁰³ is C7 alkyl. In a stillfurther aspect, R¹⁰³ is C6 alkyl. In an even further aspect, R¹⁰³ is C5alkyl. In a still further aspect, R¹⁰³ is C4 alkyl.

In a further aspect, R¹⁰³ is Ar¹⁰¹.

d. R¹⁰⁴ Groups

In one aspect, R¹⁰⁴ is selected from C1-C4 alkoxy and phenyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, R¹⁰⁴is selected from C1-C4 alkoxy and phenyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, R¹⁰⁴ is selectedfrom C1-C4 alkoxy and phenyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, R¹⁰⁴ is selected from C1-C4 alkoxy and phenylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In an even further aspect, R¹⁰⁴ is selectedfrom C1-C4 alkoxy and unsubstituted phenyl.

In a further aspect, R¹⁰⁴ is selected from —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)CH₃, and phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In a still further aspect, R¹⁰⁴ is selected from —OCH₃,—OCH₂CH₃, and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino. In yet a further aspect, R¹⁰⁴ is selected from —OCH₂CH₃and phenyl substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In aneven further aspect, R¹⁰⁴ is selected from —OCH₃ and phenyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino.

In a further aspect, R¹⁰⁴ is C1-C4 alkoxy. In a still further aspect,R¹⁰⁴ is selected from methoxy, ethoxy, n-propoxy, and isopropoxy. In yeta further aspect, R⁴ is selected from methoxy and ethoxy. In an evenfurther aspect, R¹⁰⁴ is isopropoxy. In a still further aspect, R¹⁰⁴ isethoxy. In yet a further aspect, R¹⁰⁴ is methoxy.

In a further aspect, R¹⁰⁴ is phenyl substituted with 0, 1, 2, or 3groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In a still further aspect, R¹⁰⁴ is phenylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect,R¹⁰⁴ is phenyl substituted with 0 or 1 group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect,R¹⁰⁴ is phenyl monosubstituted with a group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect,R¹⁰⁴ is unsubstituted phenyl.

In a further aspect, R¹⁰⁴ and —OR¹⁰⁵ are the same. In a still furtheraspect, R¹⁰⁴ and —OR¹⁰⁵ are different.

e. R¹⁰⁵ Groups

In one aspect, R¹⁰⁵ is C1-C4 alkyl. In a further aspect, R¹⁰⁵ isselected from methyl, ethyl, n-propyl, and isopropyl. In a still furtheraspect, R¹⁰⁵ is selected from methyl and ethyl. In yet a further aspect,R¹⁰⁵ is isopropyl. In an even further aspect, R¹⁰⁵ is ethyl. In a stillfurther aspect, R¹⁰⁵ is methyl.

f. R^(120A), R^(120B), R^(120C), R^(120D), and R^(120E) Groups

In one aspect, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) are independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a furtheraspect, each of R^(120a), R^(120b), R^(120d), and R^(120e) is hydrogen.

In a further aspect, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) is independently selected from hydrogen, —F, —Br, —Cl, —NO₂,—CN, —OH, —SH, —NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl,propenyl, ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F,—CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH,—CH₂CH₂CH₂SH, —CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,—CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)CH₂CH₃, and phenyl. In a still furtheraspect, each of R^(120a), R^(102b), R^(120c), R^(120d), and R^(120e) isindependently selected from hydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH,—OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH,—CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, and phenyl. In yet a further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F,—CHF₂, —CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F,—OCH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, and phenyl.

In various aspects, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) are independently selected from hydrogen, halogen, —NO₂, —CN,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Br, —Cl, —NO₂, —CN, —NH₂, methyl, ethyl, n-propyl,isopropyl, ethyenyl, propenyl, ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN,—CH(CH₃)CH₂CN, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)CH₂CH₃, and phenyl. In a still further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Br, —Cl, —NO₂, —CN, —NH₂, methyl, ethyl, ethyenyl,ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CN, —CH₂CH₂CN, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, and phenyl. In yet a further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Br, —Cl, —NO₂, —CN, —NH₂, methyl, —CH₂F, —CHF₂,—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, andphenyl.

In various aspects, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) are independently selected from hydrogen, halogen, —OH, —SH,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, and phenyl. In a further aspect, each of R^(120a), R^(120b),R^(120c), R^(120d), and R^(120e) is independently selected fromhydrogen, —F, —Br, —Cl, —OH, —SH, methyl, ethyl, n-propyl, isopropyl,ethyenyl, propenyl, ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,—CH(CH₃)CH₂SH, and phenyl. In a still further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Br, —Cl, —OH, —SH, methyl, ethyl, ethyenyl, ethynyl,—CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂OH,—CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃,—CH₂SH, —CH₂CH₂SH, and phenyl. In yet a further aspect, each ofR^(120a), R^(120b), R^(120c), R^(120d), and R^(120e) is independentlyselected from hydrogen, —F, —Br, —Cl, —OH, —SH, methyl, —CH₂F, —CHF₂,—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃, —SCH₃,—SCH₂CH₃, —CH₂SH, and phenyl.

In various aspects, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) are independently selected from hydrogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, n-propyl,isopropyl, ethyenyl, propenyl, ethynyl, propynyl, —CH₂CN, —CH₂CH₂CN,—CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH,—CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂,—N(CH₃)CH₂CH₃, and phenyl. In a still further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethyenyl,ethynyl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F,—OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂,—CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, and phenyl. In yeta further aspect, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) is independently selected from hydrogen, —NO₂, —CN, —OH, —SH,—NH₂, methyl, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃, —SCH₃, —SCH₂CH₃,—CH₂SH, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, and phenyl.

In various aspects, each of R^(120a), R^(120b), R^(120c), R^(120d), andR^(120e) are independently selected from hydrogen, halogen, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 thioalkyl, and phenyl. In a further aspect, each ofR^(120a), R^(120b), R^(120c), R^(120d), and R^(120e) is independentlyselected from hydrogen, —F, —Cl, methyl, ethyl, n-propyl, isopropyl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, and phenyl. In a still further aspect, eachof R^(120a), R^(120b), R^(120c), R^(120d), and R^(120e) is independentlyselected from hydrogen, —F, —Cl, methyl, ethyl, —OCH₃, —OCH₂CH₃, —SCH₃,—SCH₂CH₃, and phenyl. In yet a further aspect, each of R^(120a),R^(120b), R^(120c), R^(120d), and R^(120e) is independently selectedfrom hydrogen, —F, —Cl, methyl, —OCH₃, —SCH₃, and phenyl.

In a further aspect, each of R^(120a), R^(120b), R^(120d), and R^(120e)is hydrogen.

In various aspects, R^(120c) is selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a further aspect, R^(120c)is selected from —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl,n-propyl, isopropyl, ethyenyl, propenyl, ethynyl, propynyl, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F, —CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃,—CH₂CH₂Cl, —CH₂CH₂CH₂Cl, —CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN,—CH(CH₃)CH₂CN, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃,—OCH₂F, —OCH₂CH₂F, —OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃,—CH₂SH, —CH₂CH₂SH, —CH₂CH₂CH₂SH, —CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH₂CH₂NH₂, —CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)CH₂CH₃, and phenyl. In astill further aspect, R^(120c) is selected from —F, —Br, —Cl, —NO₂, —CN,—OH, —SH, —NH₂, methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH,—CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃,—CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₂CH₃)₂, and phenyl. In yet a further aspect, R^(120c) is selectedfrom —F, —Br, —C1, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂,—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃,—SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, and phenyl.

In various aspects, R^(120c) is selected from halogen, C1-C4 alkyl,C1-C4 alkoxy, C1-C4 thioalkyl, and phenyl. In a further aspect, R^(120c)is selected from —F, —Cl, methyl, ethyl, n-propyl, isopropyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃,—SCH(CH₃)CH₃, and phenyl. In a still further aspect, R^(120c) isselected from —F, —Cl, methyl, ethyl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃,and phenyl. In yet a further aspect, R^(120c) is selected from —F, —Cl,methyl, —OCH₃, —SCH₃, and phenyl.

In a further aspect, each of R^(120a), R^(120c), and R^(120e) ishydrogen.

In various aspects, each of R^(120b) and R^(120d) are independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a further aspect, each of R^(120b) andR^(120d) are independently selected from —F, —Br, —Cl, —NO₂, —CN, —OH,—SH, —NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl, propenyl,ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F,—CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH,—CH₂CH₂CH₂SH, —CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,—CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₃)CH₂CH₃, and phenyl. In a still furtheraspect, each of R^(120b) and R^(120d) are independently selected from—F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, ethyl, ethyenyl,ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl,—CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₂CH₃)₂, and phenyl. In yet a furtheraspect, each of R^(120b) and R^(120d) are independently selected from—F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂, —CF₃,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃, —SCH₃,—SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, —N(CH₃)₂, and phenyl.

In various aspects, each of R^(120b) and R^(120d) are independentlyselected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 thioalkyl, andphenyl. In a further aspect, each of R^(120b) and R^(120d) areindependently selected from —F, —Cl, methyl, ethyl, n-propyl, isopropyl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)CH₃, and phenyl. In a still further aspect, eachof R^(120b) and R^(120d) are independently selected from —F, —Cl,methyl, ethyl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, and phenyl. In yet afurther aspect, each of R^(120b) and R^(120d) are independently selectedfrom —F, —Cl, methyl, —OCH₃, —SCH₃, and phenyl.

g. R^(130A), R^(130B), R^(130C), R^(130D), and R^(130E) Groups

In one aspect, each of R^(130a), R^(130b), R^(130c), R^(130d), andR^(130e) are independently selected from hydrogen, halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, eachof R^(130a), R^(130b), R^(130c), R^(130d), and R^(130e) are hydrogen.

In a further aspect, each of R^(130a), R^(130b), R^(130c), R^(130d), andR^(130e) are independently selected from hydrogen, —F, —Br, —Cl, —NO₂,—CN, —OH, —SH, —NH₂, methyl, ethyl, n-propyl, isopropyl, ethyenyl,propenyl, ethynyl, propynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F, —CH₂CH₂CH₂F,—CH(CH₃)CH₂F, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CH₂CH₂Cl,—CH(CH₃)CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂CH₂CH₂CN, —CH(CH₃)CH₂CN, —CH₂OH,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(CH₃)CH₂OH, —OCF₃, —OCH₂F, —OCH₂CH₂F,—OCH₂CH₂CH₂F, —OCH(CH₃)CH₂F, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)CH₃,—SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)CH₃, —CH₂SH, —CH₂CH₂SH,—CH₂CH₂CH₂SH, —CH(CH₃)CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH₂CH₂NH₂,—CH(CH₃)CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)CH₃,—N(CH₃)₂, —N(CH₂CH₃)₂, and —N(CH₃)CH₂CH₃. In a still further aspect,each of R^(130a), R^(130b), R^(130c), R^(130d), and R^(130e) areindependently selected from hydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH,—NH₂, methyl, ethyl, ethyenyl, ethynyl, —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂Cl, —CHCl₂, —CCl₃, —CH₂CH₂Cl, —CH₂CN, —CH₂CH₂CN, —CH₂OH, —CH₂CH₂OH,—OCF₃, —OCH₂F, —OCH₂CH₂F, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —CH₂SH,—CH₂CH₂SH, —CH₂NH₂, —CH₂CH₂NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, and—N(CH₂CH₃)₂. In yet a further aspect, each of R^(130a), R^(130b),R^(130c), R^(130d), and R^(130e) are independently selected fromhydrogen, —F, —Br, —Cl, —NO₂, —CN, —OH, —SH, —NH₂, methyl, —CH₂F, —CHF₂,—CF₃, —CH₂Cl, —CHCl₂, —CCl₃, —CH₂CN, —CH₂OH, —OCF₃, —OCH₂F, —OCH₃,—SCH₃, —SCH₂CH₃, —CH₂SH, —CH₂NH₂, —NHCH₃, and —N(CH₃)₂.

h. Ar¹⁰¹ Groups

In one aspect, Ar¹⁰¹, when present, is selected from C6-C10 aryl andC5-C6 heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a further aspect, Ar¹⁰¹, when present, isselected from C6-C10 aryl and C5-C6 heteroaryl, and is substituted with0, 1, or 2 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is selected from C6-C10 aryl and C5-C6 heteroaryl,and is substituted with 0 or 1 group selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a furtheraspect, Ar¹⁰¹, when present, is selected from C6-C10 aryl and C5-C6heteroaryl, and is monosubstituted with a group selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In an even furtheraspect, Ar¹⁰¹, when present, is selected from C6-C10 aryl and C5-C6heteroaryl, and is unsubstituted.

In a further aspect, Ar¹⁰¹, when present, is C5-C6 heteroarylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In a still further aspect, Ar¹⁰¹, when present, is C5-C6 heteroarylsubstituted with 0, 1, or 2 groups independently selected from halogen,—NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl,C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy,C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a furtheraspect, Ar¹⁰¹, when present, is C5-C6 heteroaryl substituted with 0 or 1group selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl,C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In an even further aspect, Ar¹⁰¹, whenpresent, is C5-C6 heteroaryl monosubstituted with a group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In a still further aspect, Ar¹⁰¹, when present, is unsubstituted C5-C6heteroaryl.

In a further aspect, Ar¹⁰¹, when present, is C5 heteroaryl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is C5 heteroaryl substituted with 0, 1, or2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is C5 heteroaryl substituted with 0 or 1 group selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is C5 heteroarylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted C5 heteroaryl.

In a further aspect, Ar¹⁰¹, when present, is thiophenyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is thiophenyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is thiophenyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is thiophenylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted thiophenyl.

In a further aspect, Ar¹⁰¹, when present, is C6 heteroaryl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is C6 heteroaryl substituted with 0, 1, or2 groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is C6 heteroaryl substituted with 0 or 1 group selectedfrom halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl,C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl,C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is C6 heteroarylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted C6 heteroaryl.

In a further aspect, Ar¹⁰¹, when present, is pyridinyl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is pyridinyl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is pyridinyl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is pyridinylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted pyridinyl.

In a further aspect, Ar¹⁰¹, when present, is C6-C10 aryl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is C6-C10 aryl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is C6-C10 aryl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is C6-C10 arylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted C6-C10 aryl.

In a further aspect, Ar¹⁰¹, when present, is C6 aryl substituted with 0,1, 2, or 3 groups independently selected from halogen, —NO₂, —CN, —OH,—SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl,C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy,C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is C6 aryl substituted with 0, 1, or 2 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹, when present,is C6 aryl substituted with 0 or 1 group selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In an even furtheraspect, Ar¹⁰¹, when present, is C6 aryl monosubstituted with a groupselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl. In a still further aspect, Ar¹⁰¹, whenpresent, is unsubstituted C6 aryl.

In a further aspect, Ar¹⁰¹, when present, is C10 aryl substituted with0, 1, 2, or 3 groups independently selected from halogen, —NO₂, —CN,—OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl. In a still furtheraspect, Ar¹⁰¹, when present, is C10 aryl substituted with 0, 1, or 2groups independently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂,C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In yet a further aspect, Ar¹⁰¹,when present, is C10 aryl substituted with 0 or 1 group selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and phenyl.In an even further aspect, Ar¹⁰¹, when present, is C10 arylmonosubstituted with a group selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, and phenyl. In a still further aspect,Ar¹⁰¹, when present, is unsubstituted C10 aryl.

2. Diaryl and Arylalkyl Phosphonate Examples

In one aspect, a compound is selected from:

or a salt thereof.

In one aspect, a compound is selected from:

or a salt thereof.

In one aspect, a compound is selected from:

or a salt thereof.

In one aspect, a compound is selected from:

or a salt thereof.

3. Prophetic Diaryl and Arylalkyl Phosphonate Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. Thus, in oneaspect, a compound can be selected from:

or a salt thereof.

In one aspect, a compound can be selected from:

or a salt thereof.

D. Methods of Making N-Heterocyclic Phosphorodiamidic Acids

In one aspect, the invention relates to methods of making N-heterocyclicphosphorodiamidic acids. The N-heterocyclic phosphorodiamidic acids ofthis invention can be prepared by employing reactions as shown in thefollowing schemes, in addition to other standard manipulations that areknown in the literature, exemplified in the experimental sections orclear to one skilled in the art. For clarity, examples having a singlesubstituent are shown where multiple substituents are allowed under thedefinitions disclosed herein.

1. Route I

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, the synthesis of N-heterocyclic phosphorodiamidic acidscan begin with an ethylene derivative. Ethylene derivatives arecommercially available or readily prepared by one skilled in the art.Thus, compounds of type 1.6, and similar compounds, can be preparedaccording to reaction Scheme 1B above. Compounds of type 1.5 can beprepared by a cyclization reaction of an appropriate ethylenederivative, e.g., 1.4 as shown above. The cyclization reaction iscarried out in the presence of an appropriate phosphorous trihalide,e.g., POCl₃ as shown above, and an appropriate base, e.g.,triethylamine, in an appropriate solvent, e.g., dichloromethane, for anappropriate period of time, e.g., 12 hours. Compounds of type 1.6 can beprepared by a nucleophilic substitution reaction of an appropriatehalide, e.g., 1.5 as shown above, with a basic reagent, e.g., sodiumhydroxide as shown above. The nucleophilic substitution is carried outin the presence of an appropriate solvent, e.g., tetrahydrofuran, at anappropriate temperature, e.g., 65° C., for an appropriate period oftime, e.g., 18 hours. As can be appreciated by one skilled in the art,the above reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.1 and 1.2), can be substitutedin the reaction to provide substituted N-heterocyclic phosphorodiamidicacids similar to Formula 1.3.

2. Route II

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, the synthesis of N-heterocyclic phosphorodiamidic acidscan begin with an oxalaldehyde derivative and an amine derivative.Oxalaldehyde derivatives and amine derivatives are commerciallyavailable or readily prepared by one skilled in the art. Thus, compoundsof type 2.14, and similar compounds, can be prepared according toreaction Scheme 2B above. Compounds of type 2.10 can be prepared byimination of an appropriate amine derivative, e.g., 2.9 as shown above,with an appropriate oxalaldehyde derivative, e.g., 2.8 as shown above.The imination is carried out in the presence of an appropriate acid,e.g., formic acid, and an appropriate base, e.g., sodium sulphate, in anappropriate solvent, e.g., dichloromethane, for an appropriate amount oftime, e.g., 12 hours. Compounds of type 2.11 can be prepared byreduction of an appropriate imine, e.g., 2.10 as shown above. Thereduction is carried out in the presence of an appropriate reducingagent, e.g., lithium aluminium hydride, in an appropriate solvent, e.g.,tetrahydrofuran, for an appropriate period of time, e.g., 3 hours.Compounds of type 2.12 can be prepared by cyclization of an appropriatediamine, e.g., 2.10 as shown above. The cyclization is carried out inthe presence of an appropriate phosphorous trihalide, e.g., POCl₃ asshown above, an appropriate base, e.g., triethylamine, and anappropriate activating agent, e.g., 4-dimethylaminopyridine. Compoundsof type 2.14 can be prepared by nucleophilic substitution of anappropriate halide, e.g., 2.12 as shown above, with an appropriateamine, e.g., 2.13 as shown above. The nucleophilic substitution iscarried out at an appropriate temperature, e.g., 100° C. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type2.1, 2.2, 2.3, 2.4, 2.5, and 2.6), can be substituted in the reaction toprovide substituted N-heterocyclic phosphorodiamidic acids similar toFormula 2.7.

3. Route III

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein.

E. Methods of Making Diaryl and Arylalkyl Phosphonates

Organophosphonate compounds and their derivatives have shown a widerange of applications in medicinal chemistry (Mucha et al. (2011) J.Med. Chem. 54: 5955-5980; McGrath et al. (2013) Nat Rev Micro 11:412-419; Horsman and Zechel (2017) Chem. Rev. 117: 5704-5783),agrochemistry (Nowack, B. (2003) Water Res. 37: 2533-2546; Duke andPowles (2008) Pest Manage. Sci. 64: 319-325), and organic synthesis(Martin and Buchwald (2008)Acc. Chem. Res. 41: 1461-1473). Inparticular, diaryl phosphonates exhibit abroad spectrum of significantbiological activities such as human prostatic acid phosphataseinhibition (Schwender et al. (1996) Bioorg. Med. Chem. Lett. 6:311-314), leukocyte elastase inhibition (Durette and MacCoss (1992) U.S.Pat. No. 5,104,862), and calcium antagonistic activity (Younes et al.(1993) Eur. J. Med. Chem. 28: 943-948). They are also used for thepreparation of chemiluminescence materials (Motoyoshiya et al. (2003) J.Org. Chem. 68: 5950-5955) and flame retardants (Harada et al. (2014)E.P. Patent No. EP2681281 A1). In addition, they serve as versatilebuilding blocks for the synthesis of vinyl-based functional compoundssuch as fluorescent materials (Chiang et al. (2005) Org. Lett. 7:3717-3720) and OLED emitters (Mao et al. (2009)Mater. Chem. Phys. 115:378-384).

Although Michaelis-Arbuzov reaction represents a classic method fordiaryl phosphonate synthesis, this procedure is limited to alkyl halidesubstrates and elevated reaction temperatures (Demmer et al. (2011)Chem. Rev. 111: 7981-8006; Bhattacharya and Thyagarajan (1981) Chem.Rev. 81: 415-430; Michaelis and Kaehne (1898) Ber. Dtsch. Chem. Ges. 31:1048-1055; Arbuzov, A. (1906) J Russ. Phys. Chem. Soc 38: 687). Toovercome these limitations, much effort has been devoted to develop newsynthetic methods for constructing diaryl phosphonates. For example, theChakravarty group reported FeCl₃-mediated Friedel-Crafts-type arylationof α-hydroxy phosphonates with various arenes, which requires astoichiometric amount of FeCl₃ (Pallikonda and Chakravarty (2013) Eur.J. Org. Chem. 2013: 944-951). On the other hand, Walsh and co-workersdisclosed Pd-catalyzed deprotonative cross-coupling reaction of benzylphosphonates with aryl halides (Montel et al. (2014) Org. Lett. 16:1446-1449). This protocol, however, is restricted to only benzyldiisopropyl phosphonate substrate due to the use of nucleophilic base.Recently, the 1,6-hydrophosphonylation of para-quinone methides (p-QMs)for the construction of diaryl phosphonates under metal-free conditionswas disclosed (Arde and Vijaya Anand (2016) Org. Biomol. Chem. 14:5550-5554; Molleti and Kang (2017) Org. Lett. 19: 958-961). Nonetheless,for the facile synthesis and inherent instability of p-QMs (Saleh andTashtoush (1998) Tetrahedron 54: 14157-14177), a di-tert-butyl group onp-QM derivatives is necessary, which may decrease the synthetic value ofthe product with extra steps for removal of the protecting group.Considering the prevalent applications in many different fields, thedevelopment of an efficient, mild synthetic protocol for diarylphosphonates under metal-free conditions is highly desirable.

While the p-QMs have been extensively used in the phospha-Michaelreaction (Arde and Vijaya Anand (2016) Org. Biomol. Chem. 14: 5550-5554;Molleti and Kang (2017) Org. Lett. 19: 958-961), ortho-quinone methides(o-QMs), isomeric p-QM counterparts, have remained underexplored Michaelacceptors. Since the pioneering work by Fries and Kann in 1907 (Friesand Kann (1097) Liebigs Ann. Chem. 353: 335-356), o-QMs have beenregarded as highly versatile synthetic intermediates in organicsynthesis (Wang and Sun (2015) Synthesis 47: 3629-3644; Van De Water andPettus (2002) Tetrahedron 58: 5367-5405; Amouri and Le Bras (2002) Acc.Chem. Res. 35: 501-510; Bai et al. (2014) Acc. Chem. Res. 47:3655-3664). They have been utilized in various synthetic transformationssuch as [4+n] cycloaddition reaction (Wang et al. (2017) Org. Lett. 19:4126-4129; Wang and Sun (2017) Org. Lett. 19: 2334-2337; Jaworski andScheidt (2016) J Org. Chem. 81: 10145-10153; Deng et al. (2017) J Org.Chem. 82: 5433-5440; Jiang et al. (2017) Adv. Synth. Catal. 359: 1-7;Mei et al. (2017) Chem. Commun. 53: 2768-2771; Rodriguez et al. (2016)Org. Lett. 18: 4514-4517; Izquierdo et al. (2013) J Am. Chem. Soc. 135:10634-10637; Lv et al. (2013) Angew. Chem., Int. Ed. 52: 8607-8610; Wanget al. (2017) J Org. Chem. 82: 1790-1795), Michael addition reaction(Jaworski and Scheidt (2016) J Org. Chem. 81: 10145-10153),6π-electrocyclization (Song et al. (2017) Chem. Commun. 53: 6021-6024;Zeng et al. (2014) Chem. Sci. 5: 2277-2281; Carbone et al. (2012) J.Org. Chem. 77: 9179-9189; George et al. (2010) Org. Lett. 12: 3532-3535;Malerich et al. (2005) J. Am. Chem. Soc. 127: 6276-6283) and others (VanDe Water et al. (2002) Tetrahedron 58: 5367-5405; Bai et al. (2014) Acc.Chem. Res. 47: 3655-3664). Among the synthetic transformations, Michaeladdition reaction of o-QMs or aza-o-QMs with different nucleophiles,including carbon, nitrogen (Osipov et al. (2017) Synthesis 49:2286-2296; Veldhuyzen et al. (2001) J. Am. Chem. Soc. 123: 11126-11132),sulfur and oxygen nucleophiles (Lai et al. (2015) Org. Lett. 17:6058-6061; Lai and Sun (2016) Synlett 27: 555-558; Chatupheeraphat etal. (2016) Angew. Chem., Int. Ed. 55: 4803-4807; Guo et al. (2015)Angew. Chem., Int. Ed. 54: 4522-4526), has become an efficient syntheticstrategy for the direct synthesis of diverse ortho-hydroxybenzyl or2-aminobenzyl compounds.

Despite the successful application of carbon and various heteroatomnucleophiles (Izquierdo et al. (2013) J Am. Chem. Soc. 135: 10634-10637;Lv et al. (2013) Angew. Chem., Int. Ed. 52: 8607-8610; Lewis et al.(2015) Org. Lett. 17: 2278-2281; Huang and Hayashi (2015) J. Am. Chem.Soc. 137: 7556-7559; Luan and Schaus (2012) J. Am. Chem. Soc. 134:19965-19968; El-Sepelgy et al. (2014) Angew. Chem., Int. Ed. 53:7923-7927; Hsiao et al. (2014) Angew. Chem., Int. Ed. 53: 13258-13263;Saha et al. (2015) Chem. Commun. 51: 1461-1464; Zhao et al. (2015)Angew. Chem., Int. Ed. 54: 1910-1913; Grayson and Goodman (2015) J Org.Chem. 80: 2056-2061; Mattson and Scheidt (2007) J Am. Chem. Soc. 129:4508-4509), phospha-Michael reaction of trialkylphosphites with o-QMshas remained dormant since its discovery, due to the challenge of thein-situ transformation of P(III) to P(V) (Ibrahem et al. (2008) Adv.Synth. Catal. 350: 1875-1884; Maerten et al. (2007) J. Org. Chem. 72:8893-8903). This oxidation process is an utmost important step toestablish a catalytic cycle and typically requires extra nucleophilicadditives (Ibrahem et al. (2008) Adv. Synth. Catal. 350: 1875-1884;Maerten et al. (2007) J. Org. Chem. 72: 8893-8903), which can make thereaction more complex. In this regard, in situ generation of theadvantageous nucleophiles for the transformation of P(III) to P(V) wouldbe an ideal strategy.

With the continued efforts to develop NHP-derived catalysts,N-heterocyclic phosphorodiamidic acids (NHPAs) were synthesized andtheir exceptional catalytic activity in phospha-Michael reactionsdiscovered. Herein, the NHPA-catalyzed phospha-Michael addition reactionof o-QMs with trialkylphosphites and dialkyl phenylphosphonites for thesynthesis of diaryl phosphonates and phosphinates, respectively, isdisclosed. Without wishing to be bound by theory, this transformationdemonstrates the first diastereoselective phospha-Michael additionreaction of dialkyl phenylphosphites to o-QMs (FIG. 1).

Thus, in one aspect, the disclosed NHPAs are useful in making diaryl andarylalkyl phosphonates as further disclosed herein. The diaryl andarylalkyl phosphonates of this invention can be prepared by employingreactions as shown in the following schemes, in addition to otherstandard manipulations that are known in the literature, exemplified inthe experimental sections or clear to one skilled in the art. Forclarity, examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

1. Route I

In one aspect, quinone methides can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, the synthesis of quinone methides can begin with abenzaldehyde derivative and an alkyl or aryl halide. Benzaldehydederivatives and alkyl or aryl halides are commercially available orreadily prepared by one skilled in the art. Thus, compounds of type 4.6and similar compounds can be prepared according to reaction Scheme 4Babove. Compounds of type 4.6 can be prepared by a Grignard reaction ofan appropriate benzaldehyde derivative, e.g., 4.5 as shown above, and anappropriate alkyl or aryl halide, e.g., 4.4 as shown above. The Grignardreaction is carried out in the presence of magnesium metal and anappropriate activating agent, e.g., iodide, in an appropriate solvent,e.g., ether, for an appropriate period of time, e.g., 30 minutes,followed by addition of an appropriate solvent, e.g., tetrahydrofuran,for an appropriate period of time, e.g., 1 hour. As can be appreciatedby one skilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 4.1 and4.2), can be substituted in the reaction to provide substituted quinonemethides similar to Formula 4.3.

2. Route II

In one aspect, diaryl and arylalkyl phosphonates can be prepared asshown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, the synthesis of diaryl and arylalkyl phosphonates canbegin with a quinone methide derivative. Quinone methide derivatives arecommercially available or readily prepared by one skilled in the art.Thus, compounds of type 5.8, and similar compounds, can be preparedaccording to reaction Scheme 5B above. Compounds of type 5.8 can beprepared by a phospha-Michael addition reaction of an appropriatequinone methide derivative, e.g., 5.5 as shown above, and an appropriatetrialkyl phosphite or appropriate dialkylphenyl phosphite, e.g., 5.6 asshown above. Appropriate trialkyl phosphites and appropriatedialkylphenyl phosphites are commercially available or readily preparedby one skilled in the art. The phospha-Michael addition reaction iscarried out in the presence of an appropriate N-heterocyclicphosphorodiamidic acid as disclosed herein, e.g., 5.7 as shown above, inan appropriate solvent, e.g., dichloromethane. As can be appreciated byone skilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 5.1,5.2, 5.3, and 5.3′), can be substituted in the reaction to providesubstituted diaryl and arylalkyl phosphonates similar to Formula 5.4.

F. Additional Exemplary Methods of Using N-HeterocyclicPhosphorodiamidic Acids

Without wishing to be bound by theory, the disclosed NHPAs are useful inthe synthesis of a variety of building blocks of pharmaceuticals andbiologically significant small molecules. Thus, in various aspects, thedisclosed NHPAs are useful in synthetic reactions including, but notlimited to, the dimerization of quinone methides, the fluorination ofquinone methides, the tandem cyclization of quinone methides, andnucleophilic substitution reactions.

1. Route I

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beused to catalyze the dimerization of quinone methides as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. Amore specific example is setforth below.

In one aspect, compounds of type 6.8, and similar compounds, can beprepared according to reaction Scheme 6B above. Compounds of type 6.8can be prepared by dimerization of an appropriate quinone methide, e.g.,6.5 as shown above. Appropriate quinone methide derivatives arecommercially available or readily prepared by one skilled in the art.The dimerization is carried out in the presence of an appropriatedicarbamate, e.g., 6.6 as shown above, and an appropriate N-heterocyclicphosphorodiamidic acid as disclosed herein, e.g., 6.7 as shown above. Ascan be appreciated by one skilled in the art, the above reactionprovides an example of a generalized approach wherein compounds similarin structure to the specific reactants above (compounds similar tocompounds of type 6.1, 6.2, 6.3, and 6.3′), can be substituted in thereaction to provide substituted dimerized quinone methides similar toFormula 6.4.

2. Route II

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beused to catalyze a nucleophilic substitution reaction as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein and wherein R is alkyl, forexample, a C1-C4 alkyl, Nu is a nucleophile, and LG is a leaving group.A more specific example is set forth below.

In one aspect, compounds of type 7.8, and similar compounds, can beprepared according to reaction Scheme 7B above. Compounds of type 7.8can be prepared by nucleophilic substitution of an appropriate allylalcohol, e.g., 7.5 as shown above. Appropriate allyl alcohols arecommercially available or readily prepared by one skilled in the art.The nucleophilic substitution is carried out in the presence of anappropriate nucleophile, e.g., 7.6 as shown above, and an appropriateN-heterocyclic phosphorodiamidic acid as disclosed herein, e.g., 7.7 asshown above. As can be appreciated by one skilled in the art, the abovereaction provides an example of a generalized approach wherein compoundssimilar in structure to the specific reactants above (compounds similarto compounds of type 7.1, 7.2, and 7.3), can be substituted in thereaction to provide substituted aryl derivatives similar to Formula 7.4.

Examples of aryl derivatives that can be prepared using a disclosed NHPAcatalyst include, but are not limited to:

Thus, in one aspect, exemplary aryl derivatives that can be preparedusing a disclosed NHPA catalyst can be selected from

In a further aspect, exemplary aryl derivatives that can be preparedusing a disclosed NHPA catalyst can be selected from

3. Route III

In one aspect, substituted N-heterocyclic phosphorodiamidic acids can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein.

G. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, and/or methods disclosed herein are made and evaluated, andare intended to be purely exemplary of the invention and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers (e.g., amounts, temperature, etc.), but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C. or is at ambienttemperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Chemistry Experimental a. General Experimental

All reactions were carried out under atmospheric conditions inoven-dried glassware with magnetic stirring bar. Dry solvents (THF,toluene, and DCM) were obtained by solvent purification system underargon. All commercially available reagents were used as received withoutfurther purification. Purification of reaction products was carried outby flash column chromatography using silica gel 60 (230-400 mesh).Analytical thin layer chromatography was performed on 0.25 mmaluminum-backed silica gel 60-F plates. Visualization was accompaniedwith UV light and KMnO₄ solution. Concentration under reduced pressurerefers to the removal of volatiles using a rotary evaporator attached toa dry diaphragm pump (10-15 mm Hg) followed by pumping to a constantweight with an oil pump (<300 mTorr). Infrared (IR) spectra wererecorded on an IR spectrometer with KBr wafers or a film on KBr plate.High-resolution mass spectra (HRMS) were recorded on LCMS-IT-TOF massspectrometer using ESI (electrospray ionization). ¹H NMR spectra wererecorded in CDCl₃ on 400 MHz NMR spectrometer. The ¹H chemical shiftsare referenced to residual solvent signals at δ 7.26 (CHCl₃) or δ 0.00(TMS). ¹H NMR coupling constants (J) are reported in Hertz (Hz) andmultiplicities are indicated as follows: s (singlet), bs (broadsinglet), d (doublet), t (triplet), m (multiplet), dd (doublet ofdoublet), dt (doublet of triplet). ¹³C NMR spectra were proton decoupledand recorded in CDCl₃ on 100.5 MHz NMR spectrometer. The ¹³C chemicalshifts are referenced to solvent signals at δ 77.16 (CDCl₃). ³¹P NMRspectra were proton decoupled and recorded in CDCl₃ on 162 MHz NMRspectrometer. ³¹P chemical shifts are reported relative to 85% H₃PO₄(0.00 ppm) as an external standard.

b. General Procedure for the Synthesis of N-HeterocyclicPhosphorodiamidic Acids (NHPAs)

A rapid access to target catalysts with high tunability of electronicand steric properties is exceedingly important to facilitate thediscovery of new synthetic transformations. In order to develop highlytunable Brønsted acid catalysts, readily available ethylene diamineswere used to synthesize the NHPA. The synthesis of N-phosphonyl chloridewith various substituents proceeded smoothly with ethylene diamines andPOCl₃ in the presence of Et₃N. The hydrolysis reaction of theN-phosphonyl chloride with NaOH provided the target NHPA (Scheme 9).Without wishing to be bound by theory, this modular synthesis enablesfast approach to sterically and electronically diverse NHPAs such as,for example, NHPAs having Ph, 4-MeOPh, 4-FPh, and tert-butylsubstituents on the nitrogen atom. Notably, the NHPA with alkylsubstituents on the nitrogen atom is less stable than that with arylgroups, which can be due, for example, to the destabilization of theNHPA.

To a solution of N¹,N²-diphenylethane-1,2-diamine (1.02 g, 5.0 mmol) inanhydrous THF (20 mL) were added Et₃N (1.36 mL, 10 mmol), and POCl₃ (511μL, 5.5 mmol) at 0° C. After stirring for 24 h at room temperature, a 15N NaOH solution (0.7 mL) were added. The mixture was refluxed for 12 hat 65° C. (oil bath). After stirring for 12 h at 65° C., the reactionmixture was cooled down to room temperature and then concentrated underreduced pressure. The resulting mixture was dissolved in H₂O (10 mL),and the H₂O solution was washed with DCM (3×5 mL) and then neutralizedwith 3 N HCl to give a white precipitate. The white precipitate wasfiltered to give the pure2-hydroxy-1,3-diphenyl-1,3,2-diazaphospholidine 2-oxide (NHPA1) as awhite solid: 581 mg, 53% yield.

i. 2-Hydroxy-1,3-diphenyl-1,3,2-diazaphospholidine 2-oxide (NHPA1)

mp 235° C. (decomposed); R_(f)=0.1 (v_(DCM)/v_(MeOH)=95:5); IR v (KBr,cm⁻¹) 3414, 3059, 2958, 2904, 1600, 1500, 1288, 1176, 1126, 964, 748; ¹HNMR (400 MHz, d-DMSO) δ 7.33 (t, J=8.4 Hz, 4H), 7.19 (d, J=7.6 Hz, 4H),6.95 (t, J=7.2 Hz, 2H), 3.69 (d, J=8.4 Hz, 4H); ¹³C NMR (100.5 MHz,d-DMSO) δ 142.3 (d, J=6.7 Hz), 129.5, 121.1, 116.0 (d, J=4.5 Hz), 41.8(d, J=12.6 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 23.82 ppm; HRMS (ESI): m/zcalcd. for C₁₄H₁₅N₂O₂P ([M−H]⁻): 273.0798; Found: 273.0798.

ii. 2-Hydroxy-1,3-bis(4-methoxyphenyl)-1,3,2-diazaphospholidine 2-oxide(NHPA2)

206 mg, 15% yield; white solid; mp 217° C. (decomposed); R_(f)=0.1(v_(DCM)/v_(MeOH)=95:5); IR v (KBr, cm⁻¹) 3414, 2951, 2908, 1620, 1512,1246, 1180, 1033, 972, 817; ¹H NMR (400 MHz, d-DMSO) δ 7.09 (d, J=8.8Hz, 4H), 6.89 (d, J=8.8 Hz, 4H), 3.69 (s, 6H), 3.59 (d, J=8.84 Hz, 4H);¹³C NMR (100.5 MHz, d-DMSO) δ 154.2, 135.8 (d, J=6.0 Hz), 117.4 (d,J=4.5 Hz), 114.9, 55.7, 42.3 (d, J=12.6 Hz); ³¹P NMR (162 MHz, d-DMSO):δ 23.81 ppm; HRMS (ESI): m/z calcd. for C₁₆H₁₉N₂O₄P ([M−H]⁻): 333.1010;Found: 333.1008.

iii. 1,3-Bis(4-fluorophenyl)-2-hydroxy-1,3,2-diazaphospholidine 2-oxide(NHPA3)

1.02 g, 83% yield; white solid; mp 241° C. (decomposed); R_(f)=0.1(v_(DCM)/v_(MeOH)=95:5); IR v (KBr, cm⁻¹) 3066, 2955, 2893, 1620, 1508,1276, 1230, 1184, 972, 817; ¹H NMR (400 MHz, d-DMSO) δ 7.09 (d, J=8.8Hz, 4H), 6.89 (d, J=8.8 Hz, 4H), 3.69 (s, 6H), 3.59 (d, J=8.84 Hz, 4H);¹³C NMR (100.5 MHz, d-DMSO) δ 157.4 (d, J=235.9 Hz), 138.7 (dd, J=7.4,2.2 Hz), 117.5 (dd, J=7.4, 4.4 Hz), 116.1 (d, J=22.3 Hz), 42.2 (d,J=11.9 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 23.80 ppm; HRMS (ESI): m/zcalcd. for C₁₄H₁₃N₂O₂F₂P ([M−H]⁻): 309.0610; Found: 309.0620.

iv. 1,3-Di-tert-butyl-2-hydroxy-1,3,2-diazaphospholidine 2-oxide (NHPA4)

168 mg, 15% yield; white solid; mp 131-132° C.; R_(f)=0.1(v_(DCM)/v_(MeOH)=95:5); IR v (KBr, cm⁻¹) 3448, 2974, 2870, 1639, 1377,1226, 1126, 1060, 952; ¹H NMR (400 MHz, CDCl₃) δ 11.37 (br, 1H), 3.11(d, J=10.0 Hz, 4H), 1.34 (s, 9H); ¹³C NMR (100.5 MHz, CDCl₃) δ 52.9 (d,J=3.7 Hz), 39.8 (d, J=4.2 Hz), 28.3 (d, J=3.8 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 28.5 ppm; HRMS (ESI): m/z calcd. for C₁₀H₂₃N₂O₂P ([M−H]⁻):233.1424; Found: 233.1432.

v.1,1,1-trifluoro-n-(2-oxido-1,3-diphenyl-1,3,2-diazaphospholidin-2-yl)methanesulfonamide(Cat. A2)

To a solution of N¹,N²-diphenylethane-1,2-diamine (211 mg, 1.0 mmol) inanhydrous CH₂Cl₂ (10 mL) were added Et₃N (0.56 mL, 4.0 mmol), and POCl₃(100 μL, 1.1 mmol) at 0° C. After stirring for 24 h at room temperature,anhydrous CH₃CN (15 mL), DMAP (122 mg, 1.0 mmol) and TfNH₂ (149 mg, 1.0mmol) were added. The mixture was refluxed for 12 h at 100° C. (oilbath) and cooled to r.t. H₂O (5 mL) and CH₂Cl₂ (10 mL) were added andthe mixture washed successively with saturated NaHCO₃ (10 mL), 6 N HCl(2×5 mL), dried over anhydrous Na₂SO₄, and concentrated. The residue waswashed with small amount of CH₂Cl₂ to give pure product (A2) as a whitesolid: 213 mg, 53%; ¹H NMR (400 MHz, CDCl₃) δ 7.32-7.27 (m, 8H),7.16-7.10 (m, 2H), 4.09-4.03 (m, 2H), 3.88-3.81 (m, 2H); ¹³C NMR (100MHz, CDCl₃) δ 139.3, 129.6, 123.4, 117.5 (d, J=5.2 Hz), 42.6 (d, J=4.9Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −77.98.

c. Dimerization of Quinone Methides Via NHPAs

A dry 2 dram Vial was charged with cat. A1 (0.8 mg, 0.003 mmol),2-(hydroxy(phenyl) methyl)phenol (19.9 mg, 0.1 mmol), (E)-diethyldiazene-1,2-dicarboxylate (14.5 μL, 0.1 mmol) and anhydrous CH₂Cl₂ (0.5mL). The resulting mixture was stirred for 24 h at room temperature.After stirring for 24 h, the volatiles were removed under reducedpressure. The residue was subjected to column chromatography on silicagel to give corresponding product diethyl4-phenyl-2H-benzo[e][1,2,3]oxadiazine-2,3(4H)-dicarboxylate: 20.5 mg,58%; ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.26 (m, 6H), 7.20-7.14 (m, 1H),7.08-7.04 (m, 1H), 6.98-6.02 (m, 1H), 6.80 (d, J=8.0 Hz, 1H), 4.20-4.10(m, 4H), 1.25-1.16 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 154.3,141.7, 133.6, 128.6, 128.0, 127.3, 126.7, 117.2, 63.0, 62.3, 14.4, 14.2.

d. Nucleophilic Substitution Using NHPAs i. Synthesis of((1E,1′E)-oxybis(but-1-ene-3,1-diyl))dibenzene

A dry 2 dram Vial was charged with cat. A2 (2.4 mg, 0.003 mmol),(E)-4-phenylbut-3-en-2-ol (29.6 mg, 0.2 mmol) and anhydrous CH₂Cl₂ (1.0mL). The resulting mixture was stirred for 24 h at room temperature.After stirring for 24 h, the volatiles were removed under reducedpressure. The residue was subjected to column chromatography on silicagel to give corresponding product((1E,1′E)-oxybis(but-1-ene-3,1-diyl))dibenzene: 17.8 mg, 64%; ¹H NMR(400 MHz, CDCl₃) δ 7.45-7.19 (m, 10H), 6.56-6.46 (m, 2H), 6.23-6.07 (m,2H), 4.27-4.13 (m, 2H), 1.37-1.28 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ136.9, 136.7, 132.6, 132.1, 131.0, 130.2, 128.6, 128.5, 127.6, 127.5,126.5, 126.4, 73.4, 73.2, 22.3, 21.3.

ii. Synthesis of (E)-1-(4-phenylbut-3-en-2-yl)naphthalen-2-ol

A dry 2 dram Vial was charged with cat. A2 (2.4 mg, 0.003 mmol),(E)-4-phenylbut-3-en-2-ol (29.6 mg, 0.2 mmol), naphthalen-2-ol (29.2 mg,0.2 mmol) and anhydrous CH₂Cl₂ (1.0 mL). The resulting mixture wasstirred for 24 h at room temperature. After stirring for 24 h, thevolatiles were removed under reduced pressure. The residue was subjectedto column chromatography on silica gel to give corresponding product(E)-1-(4-phenylbut-3-en-2-yl)naphthalen-2-ol: 49.4 mg, 90%; ¹H NMR (400MHz, CDCl₃) δ 8.04 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.67 (dd,J=8.8, 1.2 Hz, 1H), 7.51-7.44 (m, 1H), 7.40-7.26 (m, 5H), 7.25-7.19 (m,1H), 7.06 (dd, J=9.2, 2.4 Hz, 1H), 6.75 (t, J=2.0 Hz, 2H), 4.64-4.61 (m,1H), 1.62 (t, J=2.0 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 152.3, 136.6,133.6, 132.5, 130.6, 129.7, 128.9, 128.8, 128.7, 127.7, 126.6, 126.4,123.1, 122.4, 121.2, 119.3, 33.5, 17.3.

iii. Synthesis of (E)-2-styryltetrahydrofuran

A dry 2 dram Vial was charged with cat. A2 (2.4 mg, 0.003 mmol),(E)-6-phenylhex-5-ene-1,4-diol (20.7 mg, 0.1 mmol) and anhydrous CH₂Cl₂(0.5 mL). The resulting mixture was stirred for 24 h at roomtemperature. After stirring for 24 h, the volatiles were removed underreduced pressure. The residue was subjected to column chromatography onsilica gel to give corresponding product (E)-2-styryltetrahydrofuran:15.3 mg, 88%; ¹H NMR (400 MHz, CDCl₃) δ 7.39 (d, J=7.3 Hz, 2H),7.36-7.29 (m, 2H), 7.25-7.20 (m, 1H), 6.60 (d, J=15.8 Hz, 1H), 6.22 (dd,J=6.6, 15.8 Hz, 1H), 4.54-4.46 (m, 1H), 4.07-3.95 (m, 1H), 3.91-3.82 (m,1H), 2.18-2.11 (m, 1H), 2.04-1.92 (m, 2H), 1.77-1.69 (m, 1H); ¹³C NMR(100 MHz, CDCl₃) δ 137.0, 130.7, 130.7, 128.7, 127.7, 126.7, 79.9, 68.4,32.6, 26.1.

e. General Procedure for the Synthesis of 2-hydroxy(phenyl)methyl)phenol1

2-((3,4-Dichlorophenyl)(hydroxy)methyl)phenol (11 as example): To asuspension of magnesium (245 mg, 10 mmol) and a crystal of iodine inanhydrous Et₂O (5 mL) was added dropwise a solution of bromobenzene (1.3mL, 10 mmol) in anhydrous Et₂O (3 mL). The reaction mixture was refluxedfor 30 min and then it was cooled down to 0° C. A solution ofsalicylaldehyde (0.35 mL, 3.3 mmol) in THF (3 mL) was added dropwise tothe reaction mixture over 15 min at 0° C. and the reaction mixture wasstirred for additional 1 h. After stirring for 1 h, saturated NH₄C1 wasadded dropwise to the reaction mixture at 0° C. and then the resultingsolution was extracted with Et₂O (3×10 mL). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by flash columnchromatograph on silica gel eluting with Hexane/EtOAc (6/1, v/v) toafford 11 as a white solid (832 mg, 94%).

i. 2-((3,4-Dichlorophenyl)(hydroxy)methyl)phenol (1l)

832 mg, 94%; white solid; mp 88-89° C.; R_(f)=0.25(v_(Hexane)/v_(EtOAc)=3:1), v_(Hexane)/v_(EtOAc) (6/1) for column; IR v(KBr, cm⁻¹) 3448, 1635, 1465, 1381, 1219, 1126, 1022, 756; ¹H NMR (400MHz, CDCl₃) δ 7.47 (d, J=2.4 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.23-7.15(m, 2H), 6.96-6.91 (m, 1H), 6.89-6.83 (m, 2H), 5.91 (s, 1H), 3.20 (br,1H); ¹³C NMR (100.5 MHz, CDCl₃) δ 154.8, 142.1, 132.7, 132.0, 130.5,129.8, 128.6, 128.1, 126.3, 125.9, 120.4, 117.3, 75.0; HRMS (ESI): m/zcalcd. for C₁₃H₁₀O₂Cl₂ ([M−H]⁻): 266.9985; Found: 266.9977.

ii. 2-((3,5-di-tert-butylphenyl)(hydroxy)methyl)phenol (1m)

237 mg (starting from 1.0 mmol salicylaldehyde), 76%; white solid; mp78-79° C.; R_(f)=0.3 (v_(Hexane)/v_(EtOAc)=3:1), v_(Hexane)/v_(EtOAc)(6/1) for column; IR v (KBr, cm⁻¹) 3421, 2962, 2866, 1604, 1458, 1361,1246, 1018, 752; ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.40 (t, J=2.0Hz, 1H), 7.24 (d, J=2.0 Hz, 2H), 7.19-7.14 (m, 1H), 6.90 (d, J=8.4 Hz,1H), 6.80-6.77 (m, 2H), 6.01 (d, J=2.4 Hz, 1H), 2.86 (d, J=2.8 Hz, 1H),1.31 (s, 18H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.8, 151.3, 140.9, 129.2,128.3, 126.7, 122.4, 121.2, 119.8, 117.1, 77.8, 34.9, 31.4; HRMS (ESI):m/z calcd. for C₂₁H₂₈O₂ ([M−H]⁻): 311.2017; Found: 311.2007.

f. General Procedure for the Synthesis of Diaryl Phosphonates 3

Diethyl ((2-hydroxyphenyl)(phenyl)methyl)phosphonate (3a as example): Amixture of alcohol 1a (20.1 mg, 0.1 mmol), triethyl phosphite 2a (17.6μL, 0.1 mmol), NHPA1 (0.4 mg, 0.015 mmol) and DCM (0.5 mL) in a 2-dramvial with a PTFE cap was stirred for 18 h at rt. After stirring for 18 hat rt, the reaction mixture was concentrated under reduced pressure. Theresidue was purified by flash column chromatography(v_(Hexane)/v_(EtOAc)=2:1 as eluent) on silica gel to give thecorresponding product 3a.

i. Diethyl ((2-hydroxyphenyl)(phenyl)methyl)phosphonate (3a)

29.3 mg, 91%; white solid; mp 125-126° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3147, 2982, 2901, 1597, 1458, 1199, 1026, 976, 756; ¹HNMR (400 MHz, CDCl₃) δ 9.03 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.33 (t,J=6.8 Hz, 2H), 7.30-7.24 (m, 1H), 7.16 (t, J=8.0 Hz, 1H), 7.07 (d, J=7.6Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 6.83 (td, J=7.6, 0.8 Hz, 1H), 4.70 (d,J=26.8 Hz, 1H), 4.14-3.78 (m, 4H), 1.30-1.10 (m, 6H); ¹³C NMR (100.5MHz, CDCl₃) δ 155.1 (d, J=6.0 Hz), 135.3 (d, J=5.2 Hz), 131.0 (d, J=8.2Hz), 129.7 (d, J=8.1 Hz), 129.0 (d, J=3.0 Hz), 128.6, 127.3 (d, J=1.4Hz), 123.3 (d, J=6.0 Hz), 120.9 (d, J=8.6 Hz), 119.5 (d, J=2.2 Hz), 63.9(d, J=7.5 Hz), 63.3 (d, J=6.7 Hz), 47.6 (d, J=135.5 Hz), 16.2 (d, J=6.0Hz), 16.1 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.72 ppm; HRMS(ESI): m/z calcd. for C₁₇H₂₁O₄P ([M−H]⁻): 319.1105; Found: 319.1113.

ii. Diethyl((2-hydroxy-5-methylphenyl)(phenyl)methyl)phosphonate (3b)

33.2 mg, 99%; white solid; mp 127-129° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3182, 2985, 1612, 1512, 1276, 1219, 1053, 1022, 972,694; ¹H NMR (400 MHz, CDCl₃) δ 8.86 (s, 1H), 7.50 (d, J=6.8 Hz, 2H),7.33 (t, J=7.2 Hz, 2H), 7.29-7.23 (m, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.89(d, J=3.6 Hz, 2H), 4.64 (d, J=26.8 Hz, 1H), 4.15-3.77 (m, 4H), 2.19 (s,3H), 1.19-1.10 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 152.8 (d, J=5.9Hz), 135.5 (d, J=5.2 Hz), 131.5 (d, J=8.2 Hz), 130.0, 129.7 (d, J=2.2Hz), 129.6 (d, J=3.0 Hz), 128.6, 127.3 (d, J=1.5 Hz), 122.8 (d, J=5.2Hz), 119.3 (d, J=2.2 Hz), 63.8 (d, J=6.7 Hz), 63.3 (d, J=7.4 Hz), 47.9(d, J=135.5 Hz), 20.5, 16.1 (d, J=6.0 Hz), 16.0 (d, J=5.9 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 31.74 ppm; HRMS (ESI): m/z calcd. for C₁₈H₂₃O₄P([M+H]⁺): 335.1407; Found: 335.1411.

iii. Diethyl((2-hydroxy-5-methoxyphenyl)(phenyl)methyl)phosphonate (3c)

33.3 mg, 95%; colorless oil; R_(f)=0.1 (v_(Hexane)/v_(EtOAc)=2:1),v_(Hexane)/v_(EtOAc) (2/1) for column; IR v (KBr, cm⁻¹) 3414, 3178,2982, 1597, 1508, 1435, 1207, 1026, 972, 698; ¹H NMR (400 MHz, CDCl₃) δ8.54 (br, 1H), 7.53-7.48 (m, 2H), 7.33 (t, J=8.4 Hz, 2H), 7.29-7.24 (m,1H), 6.92 (d, J=8.8 Hz, 1H), 6.74-6.67 (m, 2H), 4.73 (d, J=26.4 Hz, 1H),4.12-3.80 (m, 4H), 3.68 (s, 3H), 1.19-1.11 (m, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 153.6 (d, J=1.4 Hz), 148.8 (d, J=5.9 Hz), 135.2 (d, J=4.5 Hz),129.7 (d, J=8.2 Hz), 128.7, 127.4 (d, J=1.5 Hz), 124.3 (d, J=5.9 Hz),119.9 (d, J=2.2 Hz), 116.3 (d, J=8.2 Hz), 113.8 (d, J=3.0 Hz), 63.9 (d,J=7.5 Hz), 63.2 (d, J=6.7 Hz), 55.6, 47.1 (d, J=136.2 Hz), 16.2 (d,J=5.9 Hz), 16.1 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.07 ppm;HRMS (ESI): m/z calcd. for C₁₈H₂₃O₅P ([M+H]⁺): 351.1356; Found:351.1354.

iv. Diethyl((5-chloro-2-hydroxyphenyl)(phenyl)methyl)phosphonate (3d)

31.9 mg, 90%; white solid; mp 129-130° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3128, 2985, 1620, 1496, 1423, 1219, 1195, 1049, 1022,979, 698; ¹H NMR (400 MHz, CDCl₃) δ 9.18 (s, 1H), 7.50 (d, J=7.2 Hz,2H), 7.33 (t, J=7.6 Hz, 2H), 7.30-7.24 (m, 1H), 7.18 (d, J=1.6 Hz, 1H),7.09-7.04 (m, 1H), 6.85 (d, J=7.6 Hz, 1H), 4.77 (d, J=26.4 Hz, 1H),4.13-3.82 (m, 4H), 1.20-1.12 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 153.7(d, J=5.9 Hz), 135.0 (d, J=5.2 Hz), 130.2 (d, J=8.2 Hz), 129.7 (d, J=8.2Hz), 128.7, 128.6 (d, J=2.2 Hz), 127.5 (d, J=2.2 Hz), 125.1, 124.9 (d,J=5.9 Hz), 119.8 (d, J=1.5 Hz), 64.0 (d, J=7.4 Hz), 63.3 (d, J=7.5 Hz),46.1 (d, J=136.9 Hz), 16.2 (d, J=6.0 Hz), 16.1 (d, J=5.2 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 30.76 ppm; HRMS (ESI): m/z calcd. for C₁₇H₂₀O₄PCl([M+H]⁺): 355.0860; Found: 355.0853.

v. Diethyl((5-bromo-2-hydroxyphenyl)(phenyl)methyl)phosphonate (3e)

36.6 mg, 92%; white solid; mp 141-142° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3410, 3147, 2985, 1600, 1496, 1419, 1219, 1199, 1049, 1022,976, 698; ¹H NMR (400 MHz, CDCl₃) δ 9.26 (br, 1H), 7.51-7.42 (m, 2H),7.38-7.20 (m, 5H), 6.84-6.81 (m, 1H), 4.71 (dd, J=26.4, 5.4 Hz, 1H),4.15-3.82 (m, 4H), 1.22-1.13 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 154.4(d, J=6.0 Hz), 134.9 (d, J=4.5 Hz), 133.2 (d, J=8.2 Hz), 131.7 (d, J=3.0Hz), 129.6 (d, J=8.2 Hz), 128.8, 127.6 (d, J=2.3 Hz), 125.5 (d, J=5.2Hz), 120.8 (d, J=2.2 Hz), 112.4, 64.0 (d, J=7.4 Hz), 63.3 (d, J=7.4 Hz),46.8 (d, J=136.2 Hz), 16.2 (d, J=6.0 Hz), 16.1 (d, J=5.9 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 30.71 ppm; HRMS (ESI): m/z calcd. for C₁₇H₂O₄PBr([M+H]⁺): 399.0355; Found: 399.0353.

vi. Diethyl((3,5-di-tert-butyl-2-hydroxyphenyl)(phenyl)methyl)phosphonate (3f)

11.0 mg, 25%; colorless oil; R_(f)=0.3 (v_(Hexane)/v_(EtOAc)=3:1),v_(Hexane)/v_(EtOAc) (4/1) for column; IR v (KBr, cm⁻¹) 3414, 2958,1620, 1477, 1269, 1234, 1201, 1033, 964, 698; ¹H NMR (400 MHz, CDCl₃) δ8.70 (s, 1H), 7.51 (d, J=7.2 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 7.28 (t,J=6.8 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 4.80 (d,J=26.0 Hz, 1H), 4.10-3.75 (m, 4H), 1.44 (d, J=1.2 Hz, 9H), 1.18 (d,J=2.0 Hz, 9H), 1.17-1.07 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 151.6 (d,J=5.2 Hz), 142.4, 139.4, 135.5 (d, J=4.4 Hz), 130.0 (d, J=9.0 Hz),128.5, 127.1 (d, J=8.5 Hz), 125.4 (d, J=6.7 Hz), 123.6 (d, J=6.7 Hz),123.2 (d, J=3.0 Hz), 63.9 (d, J=8.2 Hz), 63.1 (d, J=6.7 Hz), 47.7 (d,J=134.7 Hz), 35.3, 34.3, 31.5, 29.9, 16.2 (d, J=6.0 Hz), 16.0 (d, J=5.9Hz); ³¹P NMR (162 MHz, CDCl₃): δ 32.27 ppm; HRMS (ESI): m/z calcd. forC₂₅H₃₇O₄P ([M+H]⁺): 433.2502; Found: 433.2505.

vii. Diethyl((2-hydroxyphenyl)(p-tolyl)methyl)phosphonate (3g)

31.4 mg, 94%; white solid; mp 127-128° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3136, 2982, 1600, 1458, 1199, 1053, 1026, 964, 756; ¹HNMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.17-7.07(m, 4H), 6.97 (d, J=8.0 Hz, 1H), 6.82 (t, J=7.6 Hz, 1H), 4.69 (d, J=26.8Hz, 1H), 4.15-3.79 (m, 4H), 2.32 (s, 3H), 1.20-1.10 (m, 6H); ¹³C NMR(100.5 MHz, CDCl₃) δ 155.0 (d, J=5.2 Hz), 140.0, 132.3 (d, J=5.2 Hz),130.9 (d, J=8.2 Hz), 129.5 (d, J=8.2 Hz), 129.3, 128.9 (d, J=3.0 Hz),123.5 (d, J=5.9 Hz), 120.8, 119.3 (d, J=2.2 Hz), 63.8 (d, J=7.4 Hz),63.1 (d, J=6.7 Hz), 47.0 (d, J=136.2 Hz), 21.0, 16.2 (d, J=5.2 Hz), 16.0(d, J=5.3 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.85 ppm; HRMS (ESI): m/zcalcd. for C₁₈H₂₃O₄P ([M−H]⁻): 333.1261; Found: 333.1263.

viii. Diethyl((2-hydroxyphenyl)(4-(methylthio)phenyl)methyl)phosphonate(3h)

32.9 mg, 90%; white solid; mp 134-135° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3151, 2982, 1597, 1492, 1458, 1199, 1060, 1018, 976,759; ¹H NMR (400 MHz, CDCl₃) δ 8.88 (s, 1H), 7.42 (d, J=8.0 Hz, 2H),7.23-7.16 (m, 3H), 7.13 (t, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.83(t, J=7.6 Hz, 1H), 4.75 (dd, J=26.4, 2.0 Hz, 1H), 4.14-3.82 (m, 4H),2.44 (d, J=2.4 Hz, 3H), 1.20-1.10 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ154.9 (d, J=6.7 Hz), 137.5, 132.3 (d, J=5.5 Hz), 130.8 (d, J=8.2 Hz),130.1 (d, J=8.2 Hz), 128.9 (d, J=2.3 Hz), 126.6, 123.2 (d, J=5.9 Hz),120.7, 118.7, 63.7 (d, J=6.6 Hz), 63.3 (d, J=6.7 Hz), 45.9 (d, J=136.2Hz), 16.2 (d, J=6.0 Hz), 16.1 (d, J=5.9 Hz), 15.7; ³¹P NMR (162 MHz,CDCl₃): δ 31.36 ppm; HRMS (ESI): m/z calcd. for C₁₈H₂₃O₄PS ([M+H]⁺):367.1127; Found: 367.1127.

ix. Diethyl((4-fluorophenyl)(2-hydroxyphenyl)methyl)phosphonate (3i)

30.4 mg, 90%; white solid; mp 143-145° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3410, 3163, 2982, 1600, 1508, 1454, 1219, 1199, 1053, 1026,976, 759; ¹H NMR (400 MHz, CDCl₃) δ 8.89 (br, 1H), 7.51-7.44 (m, 2H),7.19-7.08 (m, 2H), 7.05-6.95 (m, 3H), 6.84 (t, J=7.6 Hz, 1H), 4.71 (d,J=26.8 Hz, 1H), 4.14-3.97 (m, 2H), 3.97-3.83 (m, 2H), 1.20-1.10 (m, 6H);¹³C NMR (100.5 MHz, CDCl₃) δ 162.0 (d, J=244.9 Hz), 155.0 (d, J=6.0 Hz),131.3 (d, J=8.1 Hz), 131.2, 130.9 (d, J=8.2 Hz), 129.1 (d, J=2.3 Hz),123.1 (d, J=6.0 Hz), 120.9, 119.3 (d, J=2.2 Hz), 115.5 (d, J=21.6 Hz),63.8 (d, J=7.4 Hz), 63.3 (d, J=7.4 Hz), 46.5 (d, J=136.9 Hz), 16.2 (d,J=5.2 Hz), 16.1 (d, J=5.9 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.07 ppm;HRMS (ESI): m/z calcd. for C₁₇H₂₀O₄FP ([M−H]⁻): 337.1010; Found:337.1016.

x. Diethyl((4-chlorophenyl)(2-hydroxyphenyl)methyl)phosphonate (3j)

32.9 mg, 93%; white solid; mp 143-145° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3128, 2982, 1604, 1489, 1458, 1215, 1195, 1026, 976,763; ¹H NMR (400 MHz, CDCl₃) δ 8.81 (s, 1H), 7.44 (d, J=8.4 Hz, 2H),7.29 (d, J=8.4 Hz, 2H), 7.18-7.12 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.84(t, J=7.2 Hz, 1H), 4.73 (d, J=26.8 Hz, 1H), 4.15-3.97 (m, 2H), 3.97-3.82(m, 2H), 1.18 (t, J=7.2 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 154.9 (d, J=5.9 Hz), 134.1 (d, J=4.5 Hz), 133.2 (d, J=2.2Hz), 131.0 (d, J=7.5 Hz), 130.8 (d, J=7.5 Hz), 129.2 (d, J=2.2 Hz),128.7, 122.8 (d, J=5.2 Hz), 120.9, 119.0 (d, J=1.5 Hz), 63.8 (d, J=7.4Hz), 63.4 (d, J=6.7 Hz), 46.3 (d, J=136.9 Hz), 16.2 (d, J=5.9 Hz), 16.1(d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 30.90 ppm; HRMS (ESI): m/zcalcd. for C₁₇H₂₀O₄PCl ([M+H]⁺): 355.0860; Found: 355.0860.

xi. Diethyl([1,1′-biphenyl]-4-yl(2-hydroxyphenyl)methyl)phosphonate (3k)

33.6 mg, 85%; white solid; mp 176-177° C.; R_(f)=0.15(v_(DCM)/v_(EtOAc)=9:1), v_(D)CM/v_(EtOAc) (10/1) for column; IR v (KBr,cm⁻¹) 3414, 3097, 2985, 1600, 1485, 1458, 1215, 1195, 1049, 1018, 972,752; ¹H NMR (400 MHz, CDCl₃) δ 7.60-7.56 (m, 6H), 7.46-7.40 (m, 2H),7.34 (tt, J=7.6, 1.2 Hz, 1H), 7.21-7.15 (m, 1H), 7.10 (dt, J=8.0, 1.2Hz, 1H), 7.02 (dd, J=8.4, 1.2 Hz, 1H), 6.85 (tt, J=7.2, 1.2 Hz, 1H),4.72 (d, J=26.8 Hz, 1H), 4.14-4.00 (m, 2H), 4.00-3.84 (m, 2H), 1.23-1.16(m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.2 (d, J=5.3 Hz), 140.5, 140.1,134.3, 131.2, 131.0, 130.0 (d, J=7.4 Hz), 129.2 (d, J=2.2 Hz), 128.8,127.3 (d, J=3.7 Hz), 127.0, 123.2 (d, J=5.9 Hz), 121.0, 119.7 (d, J=1.5Hz), 63.9 (d, J=7.5 Hz), 63.4 (d, J=6.7 Hz), 47.7 (d, J=135.4 Hz), 16.2(d, J=6.0 Hz), 16.1 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.67ppm; HRMS (ESI): m/z calcd. for C₂₃H₂₅O₄P ([M+H]⁺): 397.1563; Found:397.1572.

xii. Diethyl((3,4-dichlorophenyl)(2-hydroxyphenyl)methyl)phosphonate(3l)

36.2 mg, 93%; white solid; mp 135-136° C.; R_(f)=0.25(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3144, 2985, 1597, 1485, 1458, 1384, 1219, 1195, 1030,976, 752; ¹H NMR (400 MHz, CDCl₃) δ 8.66 (br, 1H), 7.58 (d, J=0.8 Hz,1H), 7.37 (d, J=1.2 Hz, 2H), 7.27-7.21 (m, 1H), 7.18-7.12 (m, 1H), 6.93(d, J=8.4 Hz, 1H), 6.85 (t, J=7.2 Hz, 1H), 4.77 (d, J=26.4 Hz, 1H),4.14-3.98 (m, 2H), 3.98-3.86 (m, 2H), 1.20 (t, J=7.2 Hz, 3H), 1.14 (t,J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, CDCl₃) δ 154.8 (d, J=6.7 Hz), 136.1(d, J=4.5 Hz), 132.4, 131.6 (d, J=8.2 Hz), 131.4 (d, J=2.9 Hz), 130.6(d, J=7.5 Hz), 130.4, 129.3 (d, J=2.2 Hz), 129.0 (d, J=7.5 Hz), 122.2(d, J=5.2 Hz), 120.8, 118.5 (d, J=1.4 Hz), 63.7 (d, J=7.4 Hz), 63.6 (d,J=7.4 Hz), 45.1 (d, J=138.4 Hz), 16.2 (d, J=6.0 Hz), 16.1 (d, J=6.0 Hz);³¹P NMR (162 MHz, CDCl₃): δ 29.88 ppm; HRMS (ESI): m/z calcd. forC₁₇H₁₉O₄PCl₂ ([M+H]⁺): 389.0471; Found: 389.0468.

xiii.Diethyl((3,5-di-tert-butylphenyl)(2-hydroxyphenyl)methyl)phosphonate(3m)

38.0 mg, 88%; white solid; mp 137-138° C.; R_(f)=0.2(v_(Hexane)/v_(EtOAc)=3:1), v_(Hexane)/v_(EtOAc) (3/1) for column; IR v(KBr, cm⁻¹) 3414, 3167, 2962, 1597, 1485, 1458, 1195, 1053, 1026, 972,756; ¹H NMR (400 MHz, CDCl₃) δ 9.19 (d, J=2.8 Hz, 1H), 7.36-7.29 (m,3H), 7.18-7.11 (m, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.00 (dd, J=8.0, 1.2 Hz,1H), 6.84-6.78 (m, 1H), 4.68 (dd, J=26.8, 2.4 Hz, 1H), 4.07-3.73 (m,4H), 1.30 (d, J=2.4 Hz, 18H), 1.16-1.06 (m, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 155.3 (d, J=5.2 Hz), 150.8, 134.0 (d, J=5.2 Hz), 131.0 (d,J=8.2 Hz), 128.9 (d, J=3.0 Hz), 124.2 (d, J=8.2 Hz), 123.5 (d, J=5.9Hz), 121.1 (d, J=7.8 Hz), 120.8, 119.6 (d, J=2.2 Hz), 63.8 (d, J=7.4Hz), 63.2 (d, J=7.4 Hz), 48.4 (d, J=134.8 Hz), 34.8, 31.4, 16.2 (d,J=6.0 Hz), 16.1 (d, J=5.3 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 32.05 ppm;HRMS (ESI): m/z calcd. for C₂₅H₃₇O₄P ([M+H]⁺): 433.2502; Found:433.2505.

xiv. Diethyl((2-hydroxyphenyl)(2-methoxyphenyl)methyl)phosphonate (3n)

22.3 mg, 64%; white solid; mp 144-145° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3144, 2985, 1600, 1492, 1458, 1249, 1195, 1030, 968,756; ¹H NMR (400 MHz, CDCl₃) δ 9.00 (s, 1H), 7.89 (d, J=7.6 Hz, 1H),7.29-7.23 (m, 1H), 7.17-7.10 (m, 2H), 7.03-6.96 (m, 2H), 6.87 (d, J=8.4Hz, 1H), 6.80 (td, J=7.2, 0.4 Hz, 1H), 5.30 (d, J=26.4 Hz, 1H),4.08-3.75 (m, 4H), 3.80 (s, 3H), 1.16-1.06 (m, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 156.4 (d, J=10.4 Hz), 155.3 (d, J=5.9 Hz), 130.7 (d, J=4.5 Hz),130.6, 128.7 (d, J=3.0 Hz), 128.6 (d, J=1.5 Hz), 124.0 (d, J=3.0 Hz),123.3 (d, J=5.2 Hz), 120.7 (d, J=1.5 Hz), 120.6 (d, J=1.5 Hz), 119.3 (d,J=2.2 Hz), 110.9, 63.8 (d, J=7.4 Hz), 63.0 (d, J=6.7 Hz), 55.7, 38.3 (d,J=138.5 Hz), 16.1 (d, J=6.0 Hz), 16.0 (d, J=5.9 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 32.55 ppm; HRMS (ESI): m/z calcd. for C₁₈H₂₃O₅P ([M+H]⁺):351.1356; Found: 351.1350.

xv. Diethyl((2-hydroxyphenyl)(naphthalen-2-yl)methyl)phosphonate (3o)

27.8 mg, 75%; white solid; mp 166-168° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3147, 2982, 1597, 1458, 1222, 1195, 1053, 1022, 976,752; ¹H NMR (400 MHz, CDCl₃) δ 9.05 (s, 1H), 8.00 (s, 1H), 7.85-7.79 (m,3H), 7.59 (dd, J=8.8, 0.8 Hz, 1H), 7.50-7.44 (m, 2H), 7.20-7.14 (m, 1H),7.09 (dd, J=7.6, 1.2 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.82 (t, J=7.6 Hz,1H), 4.87 (d, J=26.8 Hz, 1H), 4.14-3.80 (m, 4H), 1.20-1.11 (m, 6H); ¹³CNMR (100.5 MHz, CDCl₃) δ 155.1 (d, J=5.2 Hz), 133.4, 132.8 (d, J=4.4Hz), 132.5 (d, J=1.5 Hz), 131.1 (d, J=7.4 Hz), 129.1 (d, J=2.2 Hz),128.6 (d, J=8.9 Hz), 128.3, 128.0, 127.7 (d, J=8.1 Hz), 127.5, 126.1 (d,J=8.2 Hz), 123.4 (d, J=6.0 Hz), 121.0, 119.6 (d, J=2.2 Hz), 64.0 (d,J=7.4 Hz), 63.3 (d, J=7.5 Hz), 47.9 (d, J=135.5 Hz), 16.2 (d, J=5.2 Hz),16.1 (d, J=5.2 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 31.64 ppm; HRMS (ESI):m/z calcd. for C₂₁H₂₃O₄P ([M+H]⁺): 371.1407; Found: 371.1394.

xvi. Diethyl((2-hydroxyphenyl)(thiophen-3-yl)methyl)phosphonate (3p)

25.4 mg, 78%; white solid; mp 180-181° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc)=2:1), v_(Hexane)/v_(EtOAc) (2/1) for column; IR v(KBr, cm⁻¹) 3414, 3140, 2985, 1604, 1458, 1195, 1053, 1026, 979, 756; ¹HNMR (400 MHz, CDCl₃) δ 9.03 (br, 1H), 7.30 (dt, J=5.2, 0.8 Hz, 1H), 7.26(s, 1H), 7.21-7.16 (m, 2H), 7.00 (dd, J=8.4, 1.2 Hz, 1H), 6.96 (dd,J=5.6, 1.2 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 5.22 (d, J=27.2 Hz, 1H),4.16-3.84 (m, 4H), 1.21-1.15 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ 155.0(d, J=4.5 Hz), 132.1 (d, J=6.7 Hz), 131.0 (d, J=8.2 Hz), 129.5 (d, J=2.2Hz), 129.2 (d, J=1.4 Hz), 126.1 (d, J=2.3 Hz), 122.1, 121.0, 119.8 (d,J=2.3 Hz), 112.0 (d, J=2.6 Hz), 64.3 (d, J=7.5 Hz), 63.8 (d, J=6.7 Hz),42.9 (d, J=141.7 Hz), 16.2 (d, J=6.0 Hz), 16.1 (d, J=5.9 Hz); ³¹P NMR(162 MHz, CDCl₃): δ 29.26 ppm; HRMS (ESI): m/z calcd. for C₁₅H₁₉O₄PS([M+H]⁺): 327.0814; Found: 327.0810.

xvii. Diethyl(1-(2-hydroxyphenyl)pentyl)phosphonate (3q)

25.8 mg, 86%; colorless oil; R_(f)=0.15 (v_(Hexane)/v_(EtOAc)=2:1),v_(Hexane)/v_(EtOAc) (2/1) for column; IR v (KBr, cm⁻¹) 3410, 3182,2958, 1600, 1458, 1222, 1199, 1057, 1030, 968, 752; ¹H NMR (400 MHz,CDCl₃) δ 8.78 (s, 1H), 7.21-7.14 (m, 1H), 7.03 (dd, J=7.6, 1.2 Hz, 1H),6.96 (d, J=8.0 Hz, 1H), 6.86 (td, J=7.6, 0.8 Hz, 1H), 4.16-4.06 (m, 2H),4.03-3.92 (m, 1H), 3.84-3.73 (m, 1H), 3.17-3.04 (m, 1H), 2.24-2.10 (m,1H), 2.01-1.08 (m, 1H), 1.40-1.07 (m, 10H), 0.84 (t, J=6.8 Hz, 3H); ¹³CNMR (100.5 MHz, CDCl₃) δ 155.7 (d, J=5.2 Hz), 131.3, 128.8 (d, J=3.0Hz), 122.1 (d, J=8.0 Hz), 120.6, 119.5 (d, J=3.0 Hz), 63.3 (d, J=6.7Hz), 62.6 (d, J=7.4 Hz), 29.9 (d, J=4.1 Hz), 26.3 (d, J=3.0 Hz), 22.2,16.4 (d, J=5.9 Hz), 16.1 (d, J=5.3 Hz), 13.8; ³¹P NMR (162 MHz, CDCl₃):δ 35.76 ppm; HRMS (ESI): m/z calcd. for C₁₅H₂₅O₄P ([M+H]⁺): 301.1563;Found: 301.1569.

xviii. Diethyl(1-(2-hydroxyphenyl)-2-phenylethyl)phosphonate (3r)

26.0 mg, 78%; colorless oil; R_(f)=0.2 (v_(Hexane)/v_(EtOAc)≤2:1),v_(Hexane)/v_(EtOAc) (2/1) for column; IR v (KBr, cm⁻¹) 3410, 3167,2982, 1600, 1458, 1222, 1199, 1057, 1030, 968, 752; ¹H NMR (400 MHz,CDCl₃) δ 8.93 (br, 1H), 7.17-7.07 (m, 4H), 7.00 (d, J=7.2 Hz, 2H), 6.95(d, J=8.0 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.70 (t, J=7.2 Hz, 1H),4.18-4.09 (m, 2H), 4.02-3.90 (m, 1H), 3.78-3.66 (m, 1H), 3.47-3.28 (m,3H), 1.34 (t, J=7.2 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz,CDCl₃) δ 155.7 (d, J=5.2 Hz), 138.9 (d, J=5.9 Hz), 131.7 (d, J=8.2 Hz),129.0 (d, J=3.0 Hz), 128.8, 128.1, 126.2, 121.6 (d, J=5.9 Hz), 120.6,119.5 (d, J=3.0 Hz), 63.6 (d, J=6.7 Hz), 62.7 (d, J=7.4 Hz), 33.1 (d,J=2.2 Hz), 16.3 (d, J=6.0 Hz), 16.1 (d, J=5.2 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 34.64 ppm; HRMS (ESI): m/z calcd. for C₁₈H₂₃O₄P ([M−H]⁻):333.1261; Found: 333.1254.

xix. Diethyl 2-hydroxybenzylphosphonate (3s)

22.0 mg, 91%; colorless oil; R_(f)=0.15 (v_(Hexane)/v_(EtOAc)=2:1),v_(Hexane)/v_(EtOAc) (2/1) for column; IR v (KBr, cm) 3410, 3182, 2985,1597, 1458, 1265, 1219, 1053, 1026, 968, 756; ¹H NMR (400 MHz, CDCl₃) δ8.57 (br, 1H), 7.16 (tt, J=7.6, 2.0 Hz, 1H), 7.06 (dt, J=7.6, 1.6 Hz,1H), 6.97 (d, J=8.4 Hz, 1H), 6.86 (t, J=7.6 Hz, 1H), 4.14-3.96 (m, 4H),3.19 (d, J=20.8 Hz, 2H), 1.25 (t, J=6.8 Hz, 6H); ¹³C NMR (100.5 MHz,CDCl₃) δ 155.6, 131.3 (d, J=8.2 Hz), 128.9 (d, J=3.7 Hz), 120.8 (d,J=3.0 Hz), 118.9 (d, J=3.0 Hz), 118.6 (d, J=8.9 Hz), 63.0 (d, J=7.4 Hz),29.9 (d, J=137.7 Hz), 16.3 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ32.74 ppm; HRMS (ESI): m/z calcd. for CH₁₇O₄P ([M−H]⁻): 243.0792; Found:243.0791.

xx. Dimethyl((2-hydroxyphenyl)(phenyl)methyl)phosphonate (3u)

29.1 mg, 99%; white solid; mp 162-163° C.; R_(f)=0.15(v_(Hexane)/v_(EtOAc) 1:1), v_(Hexane)/v_(EtOAc) (1/1) for column; IR v(KBr, cm⁻¹) 3414, 3136, 2955, 1600, 1492, 1458, 1219, 1195, 1037, 1026,833, 763; ¹H NMR (400 MHz, CDCl₃) δ 7.52-7.47 (m, 2H), 7.35 (t, J=7.2Hz, 2H), 7.31-7.27 (m, 1H), 7.21-7.15 (m, 1H), 7.08 (dt, J=7.6, 1.6 Hz,1H), 7.00 (d, J=7.6 Hz, 1H), 6.85 (t, J=7.6 Hz, 1H), 4.72 (d, J=26.8 Hz,1H), 3.64 (d, J=10.8 Hz, 3H), 3.59 (d, J=10.8 Hz, 3H); ¹³C NMR (100.5MHz, CDCl₃) δ 155.0 (d, J=5.2 Hz), 135.0, 131.1 (d, J=8.2 Hz), 129.6 (d,J=8.2 Hz), 129.2 (d, J=2.3 Hz), 128.8, 127.5 (d, J=1.4 Hz), 123.0 (d,J=6.0 Hz), 121.1, 119.6 (d, J=2.2 Hz), 54.4 (d, J=7.5 Hz), 53.6 (d,J=7.4 Hz), 47.2 (d, J=135.4 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 33.87 ppm;HRMS (ESI): m/z calcd. for C₁₅H₁₇O₄P ([M−H]⁻): 291.0792; Found:291.0792.

xxi. Diisopropyl((2-hydroxyphenyl)(phenyl)methyl)phosphonate (3v)

32.7 mg, 94%; white solid; mp 172-173° C.; R_(f)=0.5(v_(Hexane)/v_(EtOAc)=1:1), v_(Hexane)/v_(EtOAc) (1/1) for column; IR v(KBr, cm⁻¹) 3414, 3128, 2982, 1600, 1458, 1211, 1192, 1014, 995, 756; ¹HNMR (400 MHz, CDCl₃) δ 9.28 (s, 1H), 7.50 (dd, J=8.0, 1.2 Hz, 2H), 7.32(t, J=7.2 Hz, 2H), 7.28-7.23 (m, 1H), 7.15 (t, J=8.0 Hz, 1H), 7.05 (d,J=7.6 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.81 (td, J=7.6, 1.2 Hz, 1H),4.65 (d, J=26.8 Hz, 1H), 4.65-4.45 (m, 2H), 1.30 (d, J=6.4 Hz, 3H), 1.22(d, J=6.4 Hz, 3H), 0.97 (t, J=6.4 Hz, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ155.2 (d, J=6.0 Hz), 135.7 (d, J=4.5 Hz), 131.1 (d, J=8.2 Hz), 129.8 (d,J=8.2 Hz), 128.9 (d, J=3.0 Hz), 128.5, 127.2 (d, J=2.2 Hz), 123.6 (d,J=6.0 Hz), 120.7 (d, J=1.5 Hz), 119.4 (d, J=3.0 Hz), 72.8 (d, J=7.4 Hz),72.2 (d, J=7.4 Hz), 48.4 (d, J=136.9 Hz), 24.2 (d, J=3.0 Hz), 24.0 (d,J=3.0 Hz), 23.2 (d, J=5.2 Hz), 23.1 (d, J=5.2 Hz); ³¹P NMR (162 MHz,CDCl₃): δ 30.07 ppm; HRMS (ESI): m/z calcd. for C₁₉H₂₅O₄P ([M−H]⁻):347.1418; Found: 347.1420.

g. General Procedure for the Synthesis of Mixed Phosphinates 4

Methyl ((2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate (4a asexample): A mixture of alcohol 1 (20.2 mg, 0.1 mmol), dimethylphenylphosphonite 2d (173 mg, 0.1 mmol), NHPA1 (0.4 mg, 0.015 mmol) andDCM (0.5 mL) in a 2-dram vial with a PTFE cap was stirred for 18 h atrt. After stirring for 18 h, the reaction mixture was concentrated underreduced pressure. The residue was purified by flash columnchromatography (v_(DCM)/v_(EtOAc)=9:1 as eluent) on silica gel to givethe product 4a.

i. Methyl((2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate (4a)

28.7 mg, 85% with dr=4:1; white solid; mp 212-213° C.; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3163, 2951, 1597, 1454, 1188, 1033, 752; ¹H NMR (400 MHz,d-DMSO) (peaks of the major isomer) δ 9.66 (s, 1H), 7.91 (dd, J=7.6, 1.2Hz, 1H), 7.60-7.49 (m, 3H), 7.46-7.39 (m, 2H), 7.30-7.24 (m, 2H),7.16-7.04 (m, 4H), 6.87-6.78 (m, 2H), 5.10 (d, J=17.2 Hz, 1H), 3.41 (d,J=10.8 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the major isomer)δ 155.1 (d, J=8.2 Hz), 137.2, 132.7, 132.2 (d, J=8.9 Hz), 130.9, 130.3(d, J=5.2 Hz), 130.0 (d, J=6.7 Hz), 128.8 (d, J=11.9 Hz), 128.5, 128.4,127.0, 124.3 (d, J=5.2 Hz), 119.4, 115.7, 51.8 (d, J=6.7 Hz), 44.1 (d,J=96.7 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.95 ppm; HRMS (ESI): m/zcalcd. for C₂₀H₁₉O₃P ([M+H]⁺): 339.1145; Found: 339.1140.

ii. Ethyl((2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate (4b)

29.5 mg, 84% with dr=3:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3063, 2978, 1593, 1454, 1180, 1030, 960, 756; ¹H NMR (400MHz, d-DMSO) (peaks of the major isomer) δ 9.62 (s, 1H), 7.72-7.88 (m,1H), 7.57-7.44 (m, 3H), 7.41-7.34 (m, 2H), 7.27-7.23 (m, 2H), 7.14-7.02(m, 4H), 6.84-6.76 (m, 2H), 5.05 (d, J=17.2 Hz, 1H), 3.82-3.64 (m, 2H),1.00 (t, J=7.2 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the majorisomer) δ 155.2 (d, J=8.2 Hz), 137.3 (d, J=4.5 Hz), 132.5 (d, J=3.0 Hz),132.0 (d, J=8.9 Hz), 130.7, 130.3 (d, J=5.2 Hz), 130.0 (d, J=7.5 Hz),128.7 (d, J=12.6 Hz), 128.5, 128.3, 127.0, 124.4 (d, J=6.0 Hz), 119.3,115.7, 61.2 (d, J=6.7 Hz), 44.5 (d, J=96.0 Hz), 16.7 (d, J=5.2 Hz); ³¹PNMR (162 MHz, d-DMSO): δ 39.18 ppm; HRMS (ESI): m/z calcd. for C₂₁H₂₁O₃P([M+H]⁺): 353.1301; Found: 353.1293.

iii. Isopropyl((2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate (4c)

29.6 mg, 81% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3063, 2978, 1597, 1454, 1384, 1180, 983, 756; ¹H NMR (400MHz, d-DMSO) (peaks of the major isomer) δ 9.61 (s, 1H), 7.98-7.93 (m,1H), 7.58-7.46 (m, 3H), 7.42-7.36 (m, 2H), 7.28-7.24 (m, 2H), 7.16-7.04(m, 4H), 6.86-6.78 (m, 2H), 5.02 (d, J=16.8 Hz, 1H), 4.39-4.30 (m, 1H),1.04 (d, J=6.0 Hz, 3H), 1.00 (d, J=6.4 Hz, 3H); ¹³C NMR (100.5 MHz,d-DMSO) (peaks of the major isomer) δ 155.2 (d, J=8.2 Hz), 137.3, 132.8,132.4, 131.9 (d, J=9.7 Hz), 130.3 (d, J=5.2 Hz), 130.0 (d, J=7.4 Hz),128.6 (d, J=11.9 Hz), 128.4, 128.3, 126.9, 124.5 (d, J=6.0 Hz), 119.2,115.7, 69.8 (d, J=6.7 Hz), 44.8 (d, J=96.8 Hz), 24.2 (d, J=4.5 Hz), 24.0(d, J=3.7 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 38.09 ppm; HRMS (ESI): m/zcalcd. for C₂₂H₂₃O₃P ([M+H]⁺): 367.1458; Found: 367.1466.

iv. Methyl((2-hydroxy-5-methylphenyl)(phenyl)methyl)(phenyl)phosphinate(4d)

28.5 mg, 80% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3414, 3144, 2951, 1608, 1512, 1438, 1184, 1037, 821, 694; ¹H NMR(400 MHz, d-DMSO) (peaks of the major isomer) δ 9.42 (s, 1H), 7.66 (s,1H), 7.58-7.42 (m, 3H), 7.42-7.34 (m, 2H), 7.32-7.20 (m, 2H), 7.13-7.00(m, 3H), 6.84 (d, J=7.2 Hz, 1H), 6.67 (d, J=8.0 Hz, 1H), 5.06 (d, J=17.2Hz, 1H), 3.37 (d, J=10.8 Hz, 3H), 2.19 (s, 3H); ¹³C NMR (100.5 MHz,d-DMSO) (peaks of the major isomer) δ 152.8 (d, J=8.1 Hz), 137.3, 132.6,132.2 (d, J=9.7 Hz), 131.0, 130.7 (d, J=5.2 Hz), 130.0 (d, J=6.7 Hz),128.8 (d, J=11.9 Hz), 128.5, 127.7, 127.0 (d, J=1.5 Hz), 124.0 (d, J=5.9Hz), 119.4, 115.7, 51.8 (d, J=7.5 Hz), 44.1 (d, J=97.5 Hz), 20.9 (d,J=9.7 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.82 ppm; HRMS (ESI): m/zcalcd. for C₂₁H₂₁O₃P ([M+H]⁺): 353.1301; Found: 353.1308.

v. Methyl((5-chloro-2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate(4e)

28.3 mg, 76% with dr=4:1; white solid; mp 217-218° C.; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3063, 1593, 1512, 1496, 1423, 1188, 1030, 814, 694; ¹H NMR(400 MHz, d-DMSO) (peaks of the major isomer) δ 10.06 (s, 1H), 7.96-7.91(m, 1H), 7.64-7.50 (m, 3H), 7.48-7.40 (m, 2H), 7.30-7.23 (m, 2H),7.20-7.07 (m, 4H), 6.85 (d, J=8.4 Hz, 1H), 5.07 (dd, J=16.4, 2.0 Hz,1H), 3.44 (dt, J=11.2, 2.4 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaksof the major isomer) δ 154.2 (d, J=8.2 Hz), 136.6, 132.9, 132.2 (d,J=9.7 Hz), 131.3, 129.8 (d, J=7.4 Hz), 129.6 (d, J=4.4 Hz), 129.1, 128.9(d, J=11.8 Hz), 128.7, 127.3, 126.4 (d, J=5.9 Hz), 122.7, 117.3, 51.9(d, J=7.2 Hz), 43.8 (d, J=96.5 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.75ppm; HRMS (ESI): m/z calcd. for C₂₀H₁₈O₃PCl ([M+H]⁺): 373.0755; Found:373.0742.

vi. Methyl((5-bromo-2-hydroxyphenyl)(phenyl)methyl)(phenyl)phosphinate(4f)

30.8 mg, 74% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), DCM/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3414, 3082, 2951, 1593, 1492, 1419, 1276, 1184, 1030, 817, 694; ¹HNMR (400 MHz, d-DMSO) (peaks of the major isomer) δ 10.05 (s, 1H),8.02-7.98 (m, 1H), 7.58-7.45 (m, 3H), 7.44-7.36 (m, 2H), 7.24-7.18 (m,2H), 7.14-7.02 (m, 4H), 6.76 (d, J=8.4 Hz, 1H), 5.02 (d, J=17.2 Hz, 1H),3.40 (d, J=10.8 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the majorisomer) δ 154.6 (d, J=8.2 Hz), 136.6, 132.9, 132.4 (d, J=5.2 Hz), 132.2(d, J=8.9 Hz), 131.0, 129.8 (d, J=7.5 Hz), 129.1, 128.9 (d, J=11.9 Hz),128.7, 127.3, 127.0 (d, J=5.9 Hz), 117.9, 110.4, 52.0 (d, J=6.7 Hz),43.7 (d, J=96.8 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.74 ppm; HRMS (ESI):m/z calcd. for C₂₀H₁₈O₃PBr ([M+H]⁺): 417.0250; Found: 417.0247.

vii. Methyl((2-hydroxyphenyl)(p-tolyl)methyl)(phenyl)phosphinate (4g)

29.5 mg, 84% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3136, 2951, 1593, 1492, 1454, 1188, 1030, 748; ¹H NMR (400MHz, d-DMSO) (peaks of the major isomer) δ 9.60 (s, 1H), 7.83 (d, J=8.0Hz, 1H), 7.58-7.51 (m, 2H), 7.51-7.45 (m, 1H), 7.43-7.33 (m, 2H), 7.13(d, J=6.4 Hz, 2H), 7.02 (d, J=7.2 Hz, 1H), 6.90 (d, J=8.0 Hz, 2H), 6.77(d, J=7.6 Hz, 2H), 5.04 (d, J=16.8 Hz, 1H), 3.35 (d, J=10.8 Hz, 3H),2.11 (s, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the major isomer) δ155.0 (d, J=8.2 Hz), 136.0, 134.2, 132.6, 132.2 (d, J=8.9 Hz), 130.3 (d,J=5.2 Hz), 130.1 (d, J=5.9 Hz), 129.8 (d, J=6.7 Hz), 129.1, 128.8 (d,J=11.9 Hz), 128.3, 124.5 (d, J=5.2 Hz), 119.3, 115.7, 51.7 (d, J=6.7Hz), 43.5 (d, J=96.7 Hz), 20.9; ³¹P NMR (162 MHz, d-DMSO): δ 40.79 ppm;HRMS (ESI): m/z calcd. for C₂₁H₂₁O₃P ([M+H]⁺): 353.1301; Found:353.1297.

viii.Methyl((2-hydroxyphenyl)(4-(methylthio)phenyl)methyl)(phenyl)phosphinate(4h)

31.5 mg, 82% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3414, 3074, 2951, 1593, 1458, 1238, 1180, 1030, 752; ¹H NMR (400MHz, d-DMSO) (peaks of the major isomer) δ 9.67 (s, 1H), 7.87 (d, J=6.8Hz, 1H), 7.60-7.56 (m, 3H), 7.42-7.34 (m, 3H), 7.21 (d, J=6.8 Hz, 2H),7.03 (d, J=7.6 Hz, 2H), 6.82-6.74 (m, 2H), 5.07 (d, J=17.2 Hz, 1H), 3.40(d, J=10.4 Hz, 3H), 2.35 (s, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks ofthe major isomer) δ 155.1 (d, J=8.2 Hz), 136.8 (d, J=3.0 Hz), 133.8,132.7, 132.2 (d, J=8.9 Hz), 130.3 (d, J=5.2 Hz), 130.9, 130.4 (d, J=6.7Hz), 128.9 (d, J=11.9 Hz), 128.4, 126.0, 124.4 (d, J=5.2 Hz), 119.4,115.8, 51.8 (d, J=7.5 Hz), 43.4 (d, J=97.5 Hz), 14.9; ³¹P NMR (162 MHz,d-DMSO): δ 40.56 ppm; HRMS (ESI): m/z calcd. for C₂₁H₂₁O₃PS ([M+H]⁺):385.1022; Found: 385.1013.

ix. Methyl((4-fluorophenyl)(2-hydroxyphenyl)methyl)(phenyl)phosphinate(4i)

28.8 mg, 81% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3414, 3147, 2951, 1604, 1508, 1458, 1226, 1188, 1033, 810, 748; ¹HNMR (400 MHz, d-DMSO) (peaks of the major isomer) δ 9.65 (s, 1H), 7.87(d, J=7.6 Hz, 1H), 7.44-7.43 (m, 3H), 7.41-7.36 (m, 3H), 7.24-7.18 (m,2H), 6.94 (t, J=8.8 Hz, 2H), 6.83-6.76 (m, 2H), 5.05 (dd, J=17.2, 2.8Hz, 1H), 3.38 (dd, J=10.8, 3.2 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO)(peaks of the major isomer) δ 161.3 (d, J=241.8 Hz), 155.1 (d, J=8.2Hz), 133.4, 132.8, 132.2 (d, J=9.6 Hz), 131.8 (d, J=7.4 Hz), 130.7,130.1 (d, J=5.2 Hz), 128.9 (d, J=11.9 Hz), 128.5, 124.2 (d, J=5.2 Hz),119.5, 115.8, 115.3 (d, J=20.8 Hz), 51.9 (d, J=6.7 Hz), 43.3 (d, J=96.8Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.77 ppm; HRMS (ESI): m/z calcd. forC₂₀H₁₈O₃FP ([M+H]⁺): 357.1050; Found: 357.1051.

x.Methyl([1,1′-biphenyl]-4-yl(2-hydroxyphenyl)methyl)(phenyl)phosphinate(4j)

28.6 mg, 69% with dr=4:1; white solid; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3414, 3070, 2951, 1593, 1458, 1184, 1014, 759; ¹H NMR (400 MHz,d-DMSO) (peaks of the major isomer) δ 9.70 (br, 1H), 7.97-7.92 (m, 1H),7.66-7.59 (m, 3H), 7.58-7.53 (m, 2H), 7.48-7.35 (m, 8H), 7.35-28 (m,1H), 7.09 (t, J=8.0 Hz, 1H), 6.89-6.81 (m, 2H), 5.17 (d, J=17.2 Hz, 1H),3.43 (d, J=10.8 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the majorisomer) δ 155.1 (d, J=8.2 Hz), 139.9, 138.7, 136.5 (d, J=1.5 Hz), 132.8,132.2 (d, J=8.9 Hz), 130.9, 130.5 (d, J=6.7 Hz), 129.7, 129.3, 128.9 (d,J=11.9 Hz), 128.4, 127.7, 126.9, 126.8 (d, J=1.5 Hz), 124.3 (d, J=6.0Hz), 119.4, 115.8, 51.8 (d, J=6.7 Hz), 43.7 (d, J=97.5 Hz); ³¹P NMR (162MHz, d-DMSO): δ 40.54 ppm; HRMS (ESI): m/z calcd. for C₂₆H₂₃O₃P([M+H]⁺): 415.1458; Found: 415.1458.

xi. Methyl((2-hydroxyphenyl)(naphthalen-2-yl)methyl)(phenyl)phosphinate(4k)

22.5 mg, 58% with dr=99:1; white solid; mp 208-209° C.; R_(f)=0.3(v_(DCM)/v_(EtOAc)=9:1), v_(DCM)/v_(EtOAc) (9/1) for column; IR v (KBr,cm⁻¹) 3410, 3086, 2978, 1593, 1458, 1180, 1030, 810, 748; ¹H NMR (400MHz, d-DMSO) (peaks of the major isomer) δ 9.72 (br, 1H), 8.00 (d, J=7.6Hz, 1H), 7.80-7.66 (m, 4H), 7.64-7.56 (m, 2H), 7.52-7.34 (m, 6H), 7.09(t, J=7.2 Hz, 1H), 6.89-6.80 (m, 2H), 5.29 (d, J=17.2 Hz, 1H), 3.44 (dt,J=10.8, 4.0 Hz, 3H); ¹³C NMR (100.5 MHz, d-DMSO) (peaks of the majorisomer) δ 155.2 (d, J=8.2 Hz), 134.9, 133.0 (d, J=1.5 Hz), 132.7, 132.2(d, J=8.9 Hz), 132.0, 130.9, 130.4 (d, J=4.5 Hz), 129.7, 128.9 (d,J=11.9 Hz), 128.6, 128.5 (d, J=5.9 Hz), 128.1 (d, J=6.0 Hz), 128.0 (d,J=5.3 Hz), 127.8, 126.6, 126.3, 124.2 (d, J=6.0 Hz), 119.5, 115.8, 51.9(d, J=6.7 Hz), 44.2 (d, J=96.8 Hz); ³¹P NMR (162 MHz, d-DMSO): δ 40.57ppm; HRMS (ESI): m/z calcd. for C₂₄H₂₁O₃P ([M+H]⁺): 389.1301; Found:389.1297.

h. Purification of Diastereomers by Flash Column Chromatography

With the successful separation of diastereomers by flash columnchromatography of 4k, we tried to develop a practical columnpurification method for the efficient separation of diastereomersdescribed in FIG. 2A and FIG. 2B. We first used an eluent(v_(EtOAc)/v_(Hexane)=3:1) to separate the minor isomer, and thenswitched to a second eluent system (v_(DCM)/v_(EtOAc)=9:1) to isolatethe major isomer. This gradient column system allows the separation ofthe major diastereoisomers from the mixtures. For examples, phosphinate4a was isolated in 61% yield with 99:1 dr value by the gradient column(FIG. 2A, 4a). A pure diastereoisomer 4e was also obtained in 61% yield(FIG. 2A, 4e).

i. Mechanism Study

Nucleophilic additives are usually required in phospha-Michael reactionwith trialkylphosphites for the transformation of P(III) to P(V)(Ibrahem et al. (2008) Adv. Synth. Catal. 350: 1875-1884; Maerten et al.(2007) J Org. Chem. 72: 8893-8903). In contrast, NHPA-catalyzedphospha-Michael reaction of o-QM with P(OEt)₃ generates the targetMichael adducts without the nucleophile additives. Without wishing to bebound by theory, it was theorized that the in situ generated watermolecule, by dehydration of the o-hydroxybenzyl alcohols, can act as aninternal nucleophile to transform P(III) to P(V). To test thishypothesis, control experiments with drying agents such as molecularsieves and MgSO₄ were performed, and reduced product yields (66-78%) of3a by NMR were observed (Table 1, entries 2-4). Without wishing to bebound by theory, these outcomes strongly suggest that the water moleculeplays an important role in the reaction process.

TABLE 1

Entry Additive Yield 1 None 99 2 4 Å MS 66 3 5 Å MS 78 4 MgSO₄ 72

j. In Situ NMR Study

An in-situ NMR study of this phospha-Michael reaction of o-hydroxybenzylalcohol 1a with P(OiPr)₃ 2c was conducted in CD₂Cl₂ solvent. The ¹H NMRspectra are provided in FIG. 3A and FIG. 3B and the ¹³C NMR spectra areprovided in FIG. 4A and FIG. 4B. This NMR study also supports that theH₂O molecule serves as an internal nucleophile to generate the targetphosphonate product 3v (FIG. 3A and FIG. 4A, marked with diamond) andiPrOH (FIG. 3A and FIG. 4A, marked with star). We also observed thatboth ¹H NMR and ¹³C NMR peaks corresponding to the iPrOH increased byadding additional iPrOH to the crude reaction mixture (FIG. 3B and FIG.4B).

k. Large-Scale Synthesis of 3a

A mixture of alcohol 1a (1.0 g, 5.0 mmol), triethyl phosphite 2a (0.88mL, 0.1 mmol), NHPA1 (20 mg, 0.015 mmol) and DCM (25 mL) in a 50-mLflask was stirred for 40 h at rt. After stirring for 40 h at rt, thereaction mixture was concentrated under reduced pressure. The residuewas purified by flash column chromatography (v_(Hexane)/v_(EtOAc)=2:1 tov_(DCM)/v_(EtOAc)=10:1 as eluent) on silica gel to give thecorresponding product 3a (1.44 g, 90%).

l. Synthetic Manipulation of Phospha-Michael Adduct 3a

A representative schematic illustrating the synthetic utility of diarylphosphonate adducts is shown in FIG. 7.

i.Diethyl((3,3-dimethoxy-6-oxocyclohexa-1,4-dien-1-yl)(phenyl)methyl)phosphonate(5a)

To a solution of 3a (48.3 mg, 0.15 mmol) in MeOH (3.0 mL) was addedPhI(OAc)₂ (108 mg, 0.22 mmol) at 0° C. After stirring for 2 h, volatileswere removed under reduced pressure. The residue was purified by flashcolumn chromatography (v_(Hexane)/v_(EtOAc)=1.5/1) on silica gel to give5a (34.4 mg, 90%); colorless oil; R_(f)=0.2 (v_(Hexane)/v_(EtOAc)=1:1);IR v (KBr, cm⁻¹) 3418, 2982, 2908, 2831, 1678, 1647, 1238, 1122, 1053,1030, 968; ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.56 (m, 1H), 7.51-7.44 (m,2H), 7.34-7.24 (m, 3H), 6.78 (dt, J=10.0, 3.6 Hz, 1H), 6.27 (dd, J=10.4,2.8 Hz, 1H), 4.82 (dd, J=23.2, 2.8 Hz, 1H), 4.15-4.02 (m, 2H), 3.97-3.86(m, 1H), 3.80-3.68 (m, 1H), 3.43 (d, J=3.6 Hz, 3H), 3.34 (d, J=4.0 Hz,3H), 1.26 (td, J=7.2, 3.2 Hz, 3H), 1.07 (td, J=7.2, 3.2 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 183.0 (d, J=10.5 Hz), 143.4, 142.1 (d, J=6.7 Hz),136.4 (d, J=2.3 Hz), 134.7 (d, J=5.9 Hz), 129.5 (d, J=7.4 Hz), 129.4,128.6 (d, J=1.5 Hz), 127.4 (d, J=2.3 Hz), 93.0 (d, J=1.5 Hz), 63.1 (d,J=7.5 Hz), 62.3 (d, J=7.5 Hz), 50.5 (d, J=6.4 Hz), 40.3 (d, J=141.4 Hz),16.3 (d, J=5.9 Hz), 16.1 (d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ27.92 ppm; HRMS (ESI): m/z calcd. for C₁₉H₂₅O₆P ([M+H]⁺): 381.1462;Found: 381.1454.

ii. 2-((Diethoxyphosphoryl)(phenyl)methyl)phenyltrifluoromethanesulfonate (5b)

To a solution of 3a (48.2 mg, 0.15 mmol) and Et₃N (42 μL, 0.3 mmol) inDCM (1.0 mL) was added Tf₂O (38 μL, 0.225 mmol) at 0° C. After stirringfor 1 h, volatiles were removed under reduced pressure. The residue waspurified by flash column chromatography(v_(Hexane)/v_(EtOAc)/v_(DCM)=4/1/1) on silica gel to give 5b (52.9 mg,78%); yellow oil; R_(f)=0.3 (v_(Hexane)/v_(EtOAc)=1:1); IR v (KBr, cm⁻¹)3418, 2985, 2874, 1620, 1419, 1249, 1215, 1141, 1053, 1026, 968, 898; ¹HNMR (400 MHz, CDCl₃) δ 8.16 (dt, J=8.0, 2.0 Hz, 1H), 7.56-7.53 (m, 2H),7.40 (td, J=7.2, 1.2 Hz, 1H), 7.37-7.23 (m, 5H), 4.83 (d, J=25.2 Hz,1H), 4.06-3.76 (m, 4H), 1.17-1.08 (m, 6H); ¹³C NMR (100.5 MHz, CDCl₃) δ147.4 (d, J=11.1 Hz), 134.9 (d, J=5.9 Hz), 131.7 (d, J=5.2 Hz), 130.3(d, J=3.8 Hz), 129.6 (d, J=7.4 Hz), 129.0 (d, J=2.3 Hz), 128.7 (d, J=1.5Hz), 128.4 (d, J=2.3 Hz), 127.6 (d, J=2.3 Hz), 121.3, 118.5 (q, J=318.5Hz), 63.2 (d, J=7.4 Hz), 62.7 (d, J=6.7 Hz), 43.2 (d, J=140.7 Hz), 16.1(d, J=4.4 Hz), 16.0 (d, J=3.7 Hz); ¹⁹F NMR (376 MHz, CDCl₃): δ −73.99ppm; ³¹P NMR (162 MHz, CDCl₃): δ 26.50 ppm; HRMS (ESI): m/z calcd. forC₁₈H₂₀O₆F₃PS ([M+H]⁺): 453.0743; Found: 453.0743.

iii. Diethyl([1,1′-biphenyl]-2-yl(phenyl)methyl)phosphonate (5c)

To a solution of 5b (51.4 mg, 0.11 mmol), PhB(OH)₂ (16.4 mg, 0.13 mmol),Na₂CO₃ (47.2 mg, 0.44 mmol), H₂O (0.2 mL) in DME (1.0 mL) was addedPd(PPh₃)₄ (25.3 mg, 0.022 mmol). The reaction mixture was refluxed for24 h under nitrogen atmosphere. After refluxing for 24 h, the reactionmixture was cooled down to room temperature and diluted with H₂O. Theaqueous phase was extracted with EtOAc (3×10 mL). The combined organiclayers were washed with brine and dried over Na₂SO₄. The Na₂SO₄ wasfiltered off and the solvent was evaporated under reduced pressure. Theresidue was purified by flash column chromatography on silica gel(v_(Hexane)/v_(EtOAc)=4:1) to afford the product 5c (35.5 mg, 85%);yellow oil; R_(f)=0.3 (v_(Hexane)/v_(EtOAc)=1:1); IR v (KBr, cm) 3421,3059, 2982, 2870, 1492, 1477, 1246, 1053, 1026, 964, 752; ¹H NMR (400MHz, CDCl₃) δ 8.18 (dt, J=8.0, 1.2 Hz, 1H), 7.43-7.36 (m, 4H), 7.32-7.27(m, 3H), 7.26-7.15 (m, 6H), 4.62 (d, J=25.6 Hz, 1H), 4.00-3.66 (m, 4H),1.09 (t, J=6.8 Hz, 3H), 1.03 (t, J=6.8 Hz, 3H); ¹³C NMR (100.5 MHz,CDCl₃) δ 142.7 (d, J=11.1 Hz), 141.1, 136.9 (d, J=5.2 Hz), 134.3 (d,J=3.8 Hz), 130.3, 129.7 (d, J=4.4 Hz), 129.4, 129.3, 128.4 (d, J=1.5Hz), 128.1, 127.6 (d, J=2.2 Hz), 127.2, 126.9, 126.8, 62.6 (d, J=7.4Hz), 62.5 (d, J=6.7 Hz), 46.6 (d, J=137.7 Hz), 16.2 (d, J=6.7 Hz), 16.1(d, J=6.0 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 29.15 ppm; HRMS (ESI): m/zcalcd. for C₂₃H₂₅O₃P ([M+H]⁺): 381.1614; Found: 381.1612.

iv. 2-Hydroxy-3-phenyl-2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxide (5d)

A solution of 3a (31.8 mg, 0.1 mmol) and TMSBr (130 μL, 1.0 mmol) wasstirred for 5 h at rt. After stirring for 5 h, a mixture of H₂O/THF (1.0mL, v_(H2O)/v_(THF)=1:1) was added to the reaction mixture and thereaction mixture was stirred for 15 h. After stirring for 15 h,volatiles were removed under reduced pressure to give 5d (25.1 mg, 99%);colorless oil; R_(f)=0.2 (v_(DCM)/v_(MeOH)=95:5); IR v (KBr, cm⁻¹) 3522,3414, 1597, 1496, 1450, 1130, 1030, 956, 756; ¹H NMR (400 MHz, CD₃OD) δ7.73-7.69 (m, 1H), 7.51-7.48 (m, 2H), 7.29-7.22 (m, 2H), 7.21-7.15 (m,1H), 7.09-7.03 (m, 1H), 6.85-6.77 (m, 2H), 5.05 (d, J=24.8 Hz, 1H); ¹³CNMR (100.5 MHz, CD₃OD) δ 156.2 (d, J=9.7 Hz), 156.1 (d, J=10.5 Hz),139.4 (d, J=5.2 Hz), 138.9 (d, J=5.2 Hz), 131.2 (d, J=6.0 Hz), 131.1 (d,J=5.9 Hz), 130.9 (d, J=7.4 Hz), 130.8 (d, J=6.7 Hz), 129.3 (d, J=1.5Hz), 129.2 (d, J=1.5 Hz), 129.1 129.0, 127.8 (d, J=2.3 Hz), 127.6 (d,J=2.3 Hz), 125.8 (d, J=3.7 Hz), 125.2 (d, J=3.7 Hz), 120.4 (d, J=1.5Hz), 120.4 (d, J=1.5 Hz), 116.4, 116.3, 44.9 (d, J=137.7 Hz), 43.3 (d,J=139.1 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 25.10, 24.97 ppm; HRMS (ESI):m/z calcd. for C₁₃H₁₁O₃P ([M−H]⁻): 245.0373; Found: 245.0372.

v. Diethyl((2-(allyloxy)phenyl)(phenyl)methyl)phosphonate (5e)

To a solution of 3a (31.9 mg, 0.1 mmol) and K₂C03 (27.6, 0.2 mmol) inDMF (1.0 mL) was added 3-bromoprop-1-ene (13 μL, 0.15 mmol). Thereaction mixture was stirred for 12 h at 60° C. After stirring for 12 h,volatiles were removed under reduced pressure. The residue was purifiedby flash column chromatography (v_(Hexane)/v_(EtOAc)=2/1) on silica gelto give 5e (20.2 mg, 56%); colorless oil; R_(f)=0.38(v_(Hexane)/v_(EtOAc)=1:1); IR v (KBr, cm⁻¹) 3421, 2982, 2870, 1600,1492, 1454, 1246, 1053, 1026, 964, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.98(dt, J=8.0, 1.6 Hz, 1H), 7.55-7.50 (m, 2H), 7.30-7.24 (m, 2H), 7.22-7.16(m, 2H), 6.98 (td, J=8.0, 1.2 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.06-5.95(m, 1H), 5.38-5.36 (m, 1H), 5.28-5.23 (m, 1H), 5.15 (d, J=24.8 Hz, 1H),4.56-4.44 (m, 2H), 4.05-3.76 (m, 4H), 1.15-1.08 (m, 6H); ¹³C NMR (100.5MHz, CDCl₃) δ 155.6 (d, J=10.4 Hz), 137.0 (d, J=5.2 Hz), 133.2, 130.2(d, J=5.2 Hz), 129.7 (d, J=7.5 Hz), 128.3 (d, J=1.5 Hz), 128.1 (d, J=2.2Hz), 126.8 (d, J=2.2 Hz), 126.0, 120.9 (d, J=2.2 Hz), 117.2, 112.0,69.1, 62.4 (d, J=6.6 Hz), 41.9 (d, J=139.9 Hz), 16.2 (d, J=6.0 Hz); ³¹PNMR (162 MHz, CDCl₃): δ 29.40 ppm; HRMS (ESI): m/z calcd. for C₂₀H₂₅O₄P([M+H]⁺): 361.1563; Found: 361.1574.

vi. 2-Ethoxy-3-phenyl-2,3-dihydrobenzo[d][1,2]oxaphosphole 2-oxide (5f)

To a solution of 3a (48.0 mg, 0.15 mmol) in toluene (0.5 mL) was addedSOCl₂ (22 μL, 0.3 mmol). The reaction mixture was stirred for 5 h at 70°C. After stirring for 5 h, K₂C03 (41.9 mg, 0.3 mmol) was added to thereaction mixture and the mixture was stirred for 15 h. After stirringfor 15 h, the reaction mixture was cooled down to room temperature anddiluted with H₂O. The aqueous phase was extracted with DCM (3×10 mL).The combined organic layers were washed with brine and dried overNa₂SO₄. The Na₂SO₄ was filtered off and the solvent was evaporated underreduced pressure to give 5f (38.2 mg, 93%); colorless oil; R_(f)=0.32(v_(Hexane)/v_(EtOAc)=2:1); IR v (KBr, cm⁻¹) 3522, 2920, 1593, 1500,1456, 1130, 1030, 956, 756; ¹H NMR (400 MHz, CDCl₃) δ 7.38-7.22 (m,10H), 7.19-7.09 (m, 2H), 7.12-7.03 (m, 6H), 4.65 (d, J=21.2 Hz, 1H),4.42 (d, J=19.2 Hz, 1H), 4.38-4.28 (m, 2H), 4.06-3.93 (m, 1H), 3.77-3.66(m, 1H), 1.40 (t, J=6.4 Hz, 3H), 0.96 (td, J=7.2, 0.4 Hz, 3H); ¹³C NMR(100.5 MHz, CDCl₃) δ 153.0 (d, J=11.2 Hz), 152.7 (d, J=11.7 Hz), 134.5(d, J=6.7 Hz), 133.8 (d, J=8.9 Hz), 129.5, 129.4, 129.1 (d, J=5.9 Hz),129.0 (d, J=2.2 Hz), 128.9 (d, J=4.5 Hz), 128.8, 127.8 (d, J=3.8 Hz),127.7, 127.6 (d, J=3.7 Hz), 127.5, 127.3, 127.2 (d, J=3.0 Hz), 127.1 (d,J=3.0 Hz), 123.8 (d, J=5.9 Hz), 113.4 (d, J=6.7 Hz), 113.3 (d, J=7.4Hz), 64.4 (d, J=6.7 Hz), 63.7 (d, J=7.5 Hz), 43.9 (d, J=116.8 Hz), 43.1(d, J=119.8 Hz), 16.5 (d, J=5.2 Hz), 15.8 (d, J=5.9 Hz); ³¹P NMR (162MHz, CDCl₃): δ 31.92, 31.55 ppm; HRMS (ESI): m/z calcd. for C₁₅H₁₅O₃P([M+H]⁺): 275.0832; Found: 275.0831.

2. Optimization of Reaction Conditions

With the NHPAs in hand, the potential of NHPAs as organocatalysts inphospha-Michael reaction of 2-(hydroxy(phenyl)methyl)phenol 1a withtriethylphosphite 2a was employed to screen the optimal reactionconditions (Table 2). Briefly, an equal amount (0.1 mmol) of 1a and 2awas treated with 10 mol % of NHPA1 in DCM at rt for 18 hours. Thedesired diaryl phosphonate 3a was obtained in 99% yield by NMR and 92%isolated yield (Table 2, entry 1). Although other Brønsted acidsprovided moderate to excellent yields by NMR, they were inferior to theNHPA1 (Table 2, entries 2-7). To further optimize the reactionconditions, experiments with low catalyst loadings were carried out inwhich a quantitative yield of the target product by NMR was stillobtained with 1.5 mol % catalyst (Table 2, entries 8-9). Furthermodification of the NHPA with electron-donating groups on the nitrogenatom (entry 10 and entry 12) decreased the catalytic activity whereasthat of electron-deficient groups maintained the excellent catalyticreactivity (entry 9 and entry 11). Without wishing to be bound bytheory, these outcomes strongly support that the pK_(a) of NHPAs can besystemically modified. Known Brønsted acids NHPA5 and BPA were alsotested, but were inferior to NHPA1 (entry 9 versus entries 13-14). Amongthe solvents screened, DCM is superior to other solvents such as ether,toluene, CH₃CN, THF, CHCl₃, and EtOH (Table 2, entries 15-20). Notably,when EtOH was used as a solvent, only 26% yield of 3a by NMR wasobserved along with 72% recovered starting material without thepotential oxa-Michael adduct (Lai et al. (2015) Org. Lett. 17:6058-6061).

TABLE 2

Entry acids (x mol%) solvent yield (%)^(b) 1 NHPA1 (10.0) DCM>99(92)^(c) 2 CH₃COOH (10.0) DCM 69 3 CF₃COOH (10.0) DCM 94 44-NO₂PhCOOH (10.0) DCM 98 5 TfOH (10.0) DCM 78 6 Conc. HCl (10.0) DCM NR7 TsOH (10.0) DCM 69 8 NHPA1 (3.0) DCM >99 (91)^(c) 9 NHPA1 (1.5)DCM >99 (91)^(c) 10 NHPA2 (1.5) DCM 63 11 NHPA3 (1.5) DCM >99 (90)^(c)12 NHPA4 (1.5) DCM 90 13 NHPA5 (1.5) DCM 69 14 BPA (1.5) DCM 65 15 NHPA1(1.5) ether 65 16 NHPA1 (1.5) toluene 93 17 NHPA1 (1.5) CH₃CN 80 18NHPA1 (1.5) THF 59 19 NHPA1 (1.5) CHCl₃ 16 20 NHPA1 (1.5) EtOH 27^(a)Reaction condition: 1a (0.1 mmol), acids (x mol %) and P(OEt)³ 2a(0.1 mmol) in solvent (0.5 mL) for 18 h; NR = No Reaction ^(b)Yield wasdetermined by ¹H NMR on the crude reaction mixture using1,3,5-trimethylbenzene as an internal standard. ^(c)Isolated yield.

3. Scope of the Phospha-Michael Reaction

Having established the optimized reaction conditions (Table 2, entry 9),the scope of the reaction was investigated as described in FIG. 5. Theelectronic effects of the substrates on this transformation arenegligible whereas the steric effects significantly influence theproduct yields in this phospha-Michael reaction. For example, thereaction tolerates both electron-donating groups (Me 1b and MeO 1c) andelectron-deficient groups (Cl 1d and Br 1e) on the benzene ring,providing excellent product yields (FIG. 5, 3b-e). In addition, avariety of para-substituted benzene rings with electron-donating groups(4-Me 1g and 4-MeS 1h) or electron-withdrawing groups (F 1i, Cl 1j, and4-Ph 1k) were well tolerated, and provided the corresponding products inhigh to excellent yields (FIG. 5, 3g-k). In contrast, ortho-substitutedsubstrates 1f (4,6-di-tert-Bu) and 1n (2-MeO) provided the targetproducts in 25% and 64% yields, respectively (FIG. 5, 3f, 3n). Apolycyclic aromatic compound 10 also proved to be a suitable substrate,producing 1-naphthyl phosphonate 3o in 75% yield. A heteroaromaticsubstrate 1p also succeeded in providing the desired adduct 3p in 78%yield.

The scope of alkyl, aryl-mixed substrates was also explored. Forexample, 1q and 1r with aliphatic substituents were also suitablesubstrates for this reaction to provide the alkyl-substituted benzylphosphonates 3q, 3r in 78% and 86% yields, respectively. Saligenol iswas smoothly converted to benzyl phosphonate 3s with 91% product yield.In an effort to challenge the synthesis of tetra-substituted diarylphosphonates, diaryl methyl tertiary benzyl alcohol 1t was treated with2a and NHPA catalyst under the standard reaction conditions.Unfortunately, no target product was observed (FIG. 5, 3t). Withoutwishing to be bound by theory, this can be due to the steric hindrance.Finally, different alkylphosphites such as P(OMe)₃ 2b and P(OiPr)₃ 2cwere evaluated, and they also afforded the corresponding diarylphosphonates 3u, 3v in 99% and 94% yields, respectively.

4. Diastereoselective Synthesis of Diaryl Phosphinates

As an important corollary to the development of efficient syntheticstrategies for the NHPA-catalyzed phospha-Michael reaction using o-QMs,a new synthetic route to P-stereogenic phosphonate moieties wasenvisioned. This synthetic method involves phospha-Michael reaction ofo-QMs with dialkyl phenylphosphonites and sequential nucleophilicsubstitution to form P-chiral phosphinates. In this phosphonatechemistry field, the Montchamp group has pioneered a metal-catalyzedhydrophosphinylation of hypophosphites for the synthesis of a variety ofphosphonates over the decades (Belabassi et al. (2011) J. Organomet.Chem. 696: 106-111; Deprele and Montchamp (2004) Org. Lett. 6:3805-3808; Deprele and Montchamp (2002) J. Am. Chem. Soc. 124:9386-9387; Bravo-Altamirano et al. (2008) J. Org. Chem. 73: 2292-2301;Deal et al. (2011) Org. Lett. 13: 3270-3273; Coudray and Montchamp(2008) Eur. J. Org. Chem. 2008: 4101-4103; Coudray et al. (2008) Org.Lett. 10: 1123-1126; Petit et al. (2011) Adv. Synth. Catal. 353:1883-1888; Bravo-Altamirano et al. (2010) Org. Biomol. Chem. 8:5541-5551; Abrunhosa-Thomas et al. (2007) J. Org. Chem. 72: 2851-2856).Recently, a copper-catalyzed Michaelis-Arbuzov reaction was reported byTaillefer and co-workers as an alternative to the use of expensive andtoxic transition metals (Ballester et al. (2014) ChemCatChem 6;1549-1552). Despite the various synthetic methods for the synthesis ofphosphonates, a metal-free, organocatalytic protocol useful for thesynthesis of biologically active phosphonates (Mucha et al. (2011) JMed. Chem. 54: 5955-5980; Peck et al. (2012)Methods Enzymol. 516:101-123) has remained underdeveloped.

Having the early success in phosphonylation of o-QMs with trialkylphosphites, the reactivity of dialkyl phenylphosphonites under the samereaction conditions was explored (Table 3). This reaction allows aregio- and diastereoselective transformation, providing only1,4-addition products with good diastereoselectivity (4:1 dr). First,the scope of phosphonite nucleophiles was investigated. When dimethylphenylphosphonite 2d was employed, the target phosphinate product 4a wasisolated in 85% yield with 4:1 dr value (Table 3, entry 1). Othernucleophiles such as ethyl and isopropyl phosphonites 2e, 2f alsoprovided the desired phosphinate products 4b, 4c in 83% and 84% yieldswith 3:1 and 4:1 dr values, respectively (Table 3, entries 2-3). Next,the scope of Michael acceptors with various substituents was examined(4-Me 1b, 4-Cl 1d, 4-Br 1e, 4-Me 1g, 4-MeS 1h, 4-F 1i, 4-Ph 1j) and theyall yielded the corresponding products in good yields (Table 3, entries4-10). Without wishing to be bound by theory, these data suggestnegligible electronic effects on reactivity. Finally, a solubility-basedpurification of diastereomers was successfully demonstrated.Purification via flash column chromatography of a crude mixture of2-naphthyl phosphinate (4k) with 4:1 dr allowed the isolation of themajor diastereomer in 58% yield with 99:1 dr (Table 3, entry 11). Withthe demonstration of an efficient column purification of thediastereomers, different phosphinate products 4a-e were further examinedby performing a second column chromatography. In general, these attemptswere all successful in isolating the major diastereomers. This flashcolumn chromatography was particularly useful for the purification ofdiastereomers 4a, 4e, providing excellent selectivity (dr>99:1).

TABLE 3

Yield (%)^(b) Entry R¹⁰⁵ R^(101b) R¹⁰³ Product (dr)^(c) 1 Me H Ph 4a 85(4:1) 2 Et H Ph 4b 84 (3:1) 3 iPr H Ph 4c 83 (4:1) 4 Me Me Ph 4d 80(4:1) 5 Me Cl Ph 4e 76 (4:1) 6 Me Br Ph 4f 74 (4:1) 7 Me H 4-MePh 4g 84(4:1) 8 Me H 4-MeSPh 4h 82 (4:1) 9 Me H 4-FPh 4i 81 (4:1) 10 Me H 4-PhPh4j 69 (4:1) 11 Me H 2-NAP 4k 58 (4:1) (dr >99:1)^(d) 'Reactioncondition: 1 (0.1 mmol), 2 (0.1 mmol) and NHPA1 (1.5 mol %) in DCM (0.5mL) at rt for 18 h. ^(b)Isolated yield. ^(c)dr value of the isolatedproduct by flash column chromatography on a silica column.

5. Proposed Mechanism

To gain insights into the catalytic cycle of this transformation, aplausible mechanism was proposed on the basis of the results from thecontrol experiments (FIG. 6). The NHPA-catalyzed dehydration ofo-hydroxybenzyl alcohol 1a responses for the generation of o-QMintermediate A, which is activated by hydrogen bond with the NHPA1. Thefollowing phospha-Michael addition reaction with P(OEt)₃ 2a generates aphosphonium intermediate B, which then is attacked by H₂O nucleophile toproduce the diarylphosphonate product 3a and EtOH.

6. Synthetic Utility of Diaryl Phosphonates

To demonstrate the synthetic utility of the versatile diaryl phosphonateadducts, a large-scale experiment with 1a (1.0 g, 5.0 mmol) was tested.This experiment afforded the target Michael adduct 3a (1.44 g) in 90%yield (FIG. 7). Next, synthetic transformation of 3a was explored. Thephenol group on 1a was readily oxidized to γ-ketophosphonate 5a withPhI(OAc)₂. The conversion of the phenolic hydroxyl group 3a to thecorresponding aryl triflate 5b in presence of Tf₂O and Et₃N proceededsmoothly and the sequential Suzuki cross-coupling reaction of 5b withPhB(OH₂) delivered the target product 5c in 85% yield. McKenna reactionconditions (McKenna et al. (1977) Tetrahedron Lett. 18: 155-158) fordealkylation of the ethylphosphonate 3a provided only cyclic phosphonate5d as a potential halogen-free flame retardant (Harada et al. (2014)E.P. Patent No. EP 2681281 A1). The treatment of 3a with allyl bromideunder basic conditions afforded allyloxy substituted diaryl phosphonate5e in moderate yield. Finally, considering the significant applicationof the cyclic phosphonates as precursors of stabilized C-centeredradicals (Terada et al. (2006) Synlett 2006: 133-136), a one-potcyclization of 3a in presence of SOCl₂ and K₂C03 was conducted and thedesired cyclic phosphonate product 5f was obtained in 93% yield.

In summary, a N-heterocyclic phosphorodiamidic acid (NHPA)organocatalysts was developed for phospha-Michael reaction of o-QMs withtrialkylphosphites. This NHPA catalyst has demonstrated its highcatalytic efficiency (1.5 mol % catalyst) in phosphonylation of o-QMs tosynthesize versatile diaryl phosphonates under mild reaction conditions.In addition, this organocatalytic system enables diastereoselectivesynthesis of diaryl phosphinates employing dialkyl phenylphosphonites.Without wishing to be bound by theory, a series of control experimentsand an in-situ NMR study suggest that a water molecule generated bydehydration of o-hydroxybenzyl alcohol serves as an internal nucleophilefor the transformation of P(III) to P(V). On the basis of theseoutcomes, a plausible mechanism of the NHPA-catalyzed phospha-Michaelreaction was proposed.

H. References

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It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otheraspects of the invention will be apparent to those skilled in the artfrom consideration of the specification and practice of the inventiondisclosed herein. It is intended that the specification and examples beconsidered as exemplary only, with a true scope and spirit of theinvention being indicated by the following claims.

What is claimed is:
 1. A compound having a structure represented by aformula selected from:

wherein each occurrence of

is a single covalent bond; wherein each of R^(1a), R^(1b), R^(1a′), andR^(1b′), when present, is independently selected from hydrogen, C1-C4alkyl, and Ar¹; wherein each occurrence of Ar¹, when present, isindependently selected from C6-C14 aryl and 4-10 membered heteroaryl,and is substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; orwherein each of R^(1a) and R^(1b) are optionally covalently bondedtogether and, together with the intermediate atoms, comprise a 5- to6-membered cycloalkyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; or wherein each of R^(1a′) and R^(1b′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- to 6-membered cycloalkyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,—CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein each of R², R³,R^(2′), and R^(3′), when present, are independently selected from—Si(R^(20a))(R^(20b))R^(20c), Ar², and —C(R^(21a))(R^(21b))Ar²; whereineach occurrence of R^(20a), R^(20b); and R^(20c), when present, isindependently selected from C1-C4 alkyl and phenyl; wherein eachoccurrence of R^(21a) and R^(21b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar²,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, and phenyl; or wherein each occurrence of

is a double covalent bond; wherein each of R^(1a) and R² are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar³, and —C(R^(22a))(R^(22b))Ar³; whereineach occurrence of R^(22a) and R^(22b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein each occurrence of Ar³,when present, is independently selected from C6-C14 aryl and 4-10membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl,C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; wherein each of R^(1a′) and R^(2′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar³, and—C(R^(22a))(R^(22b))Ar³; wherein each of R^(1b) and R³ are optionallycovalently bonded together and, together with the intermediate atoms,comprise a 5- or 6-membered heterocycloalkyl substituted with 0, 1, 2,or 3 groups independently selected from halogen, —NO₂, —CN, —OH, —SH,—NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino, Ar⁴, and —C(R^(23a))(R^(23b))Ar⁴; whereineach occurrence of R^(23a) and R^(23b), when present, is independentlyselected from hydrogen and C1-C4 alkyl; wherein occurrence of Ar⁴, whenpresent, is independently selected from C6-C14 aryl and 4-10 memberedheteroaryl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4)dialkylamino; and wherein each of R^(1b′) and R^(3′), when present, areoptionally covalently bonded together and, together with theintermediate atoms, comprise a 5- or 6-membered heterocycloalkylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4 alkyl, C2-C4 alkenyl, C2-C4alkynyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4haloalkoxy, C1-C4 alkoxy, C1-C4 thioalkyl, C1-C4 alkylthiol, C1-C4aminoalkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, Ar⁴, and—C(R^(23a))(R^(23b))Ar⁴; wherein R⁴, when present, is selected from —OHand —NHR²⁴; wherein R²⁴, when present, is an amine protecting group,provided that when the compound has a structure represented by aformula:

wherein each of R^(1a) and R^(1b) are hydrogen and R² and R³ are Ar²,then each occurrence of Ar² is substituted with 1, 2, or 3 groupsindependently selected from halogen, —NO₂, —CN, —OH, —SH, —NH₂, C1-C4haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4thioalkyl, C1-C4 alkylthiol, C1-C4 aminoalkyl, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino, or wherein each of R^(1a) and R^(1b) arehydrogen, R² and R³ are independently —C(R^(21a))(R^(21b))Ar², and Ar²is unsubstituted C10 aryl, then each occurrence of R^(21a) is nothydrogen, or wherein each of R^(1a) and R^(1b) are optionally covalentlybonded together and, together with the intermediate atoms, comprise anunsubstituted 6-membered cycloalkyl, R² and R³ are independently—C(R^(21a))(R^(21b))Ar², and Ar² is unsubstituted C10 aryl, then eachoccurrence of R^(21a) is not hydrogen, or a salt thereof.
 2. Thecompound of claim 1, wherein the compound has a structure represented bya formula:


3. The compound of claim 1, wherein

is a single covalent bond.
 4. The compound of claim 1, wherein each ofR^(1a) and R^(1b) is independently selected from hydrogen and Ar¹. 5.The compound of claim 1, wherein R^(1a) and R^(1b) are the same.
 6. Thecompound of claim 1, wherein each of R^(1a) and R^(1b) are optionallycovalently bonded together and, together with the intermediate atoms,comprise an unsubstituted 6-membered cycloalkyl.
 7. The compound ofclaim 1, wherein R² and R³ are the same.
 8. The compound of claim 1,wherein each of R² and R³ are independently selected from Ar² and—C(R^(21a))(R^(21b))Ar².
 9. The compound of claim 1, wherein eachoccurrence of Ar², when present, is independently C6 aryl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NO₂,C1-C4 alkyl, and phenyl.
 10. The compound of claim 1, wherein R⁴ is —OH.11. The compound of claim 1, wherein the compound has a structurerepresented by a formula:


12. The compound of claim 1, selected from:


13. A compound selected from:

or a salt thereof.